WO2017037279A1

WO2017037279A1 - Inhibitor of dj-1 for therapy

Info

Publication number: WO2017037279A1
Application number: PCT/EP2016/070818
Authority: WO
Inventors: Feng He; Rudi BALLING; Egle DANILEVICIUTE
Original assignee: Université Du Luxembourg
Priority date: 2015-09-04
Filing date: 2016-09-05
Publication date: 2017-03-09
Also published as: LU92815B1

Abstract

The present invention relates to an Inhibitor of DJ-1 (PARK7) for use in the treatment or prevention of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer.In addition, the present invention relates to pharmaceutical compositions comprising such ihibitorsand kits comprising the inhibitor.

Description

INHIBITOR OF DJ-1 FOR THERAPY

INVENTION

[001] The present invention relates to an Inhibitor of DJ-1 (PARK7) for use in the treatment or prevention of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer. In addition, the present ivention relates to pharmaceutical compositions comprising such ihibitorsand kits comprising the inhibitor.

DESCRIPTION

[002] DJ-1 , also known as PARK7, as its name suggests, is one of the familial Parkinson's disease (PD) genes. Defects in human DJ-1 are the cause of autosomal recessive early-onset PD. DJ-1 is a redox-responsive protein and is long thought to mainly play an essential protective role in neurons. DJ-1 is a redox-responsive protein and is thought to mainly play an essential protective role in neurons (Abou-Sleiman et al. (2003); Xu et al. (2005); van der Brug et al. (2008); Kahle et al. (2009); Jeong et al. 2012)). In addition to this classical protection mode, DJ-1 also protects neurons by regulating neuro-inflammatory responses of astrocytes (Waak et al. (2009)). Thus, DJ- 1 can be used in the treatment of Parkinsons's disease.

[003] The technical problem can be seen in the provision of an alternative use of DJ- 1 . The technical problem is solved by the embodiments reflected in the claims, described in the description, and illustrated in the Examples and Figures.

[004] The present invention relates to an inhibitor of DJ-1 (PARK7) for use in the treatment or prevention of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer.

[005] The present invention also relates to an inhibitor of DJ-1 (PARK7) for use in the treatment or prevention of one or more of autoimmune disease, allergy or infectious disease.

[006] The present invdention also relates to a pharmaceutical composition comprising the inhibitor as described herein.

[007] Furthermore, the present invention relates to a use of an inhibitor of DJ-1 (PARK7) for use in the treatment or prevention of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer.

[008] The present invention also relates to a method for screening for an inhibitor or activator of DJ-1 , the method comprising

(a) contacting Tregs with a nucleic acid molecule, preferably a siRNA or a miRNA, binding protein, small molecule or compound of interest;

(b) measuring suppressor function of Tregs, wherein a increase in suppressor function of said Tregs compared to said Tregs before contacting indicates that the nucleic acid molecule, preferably a siRNA or a miRNA, binding protein, small molecule or compound of interest serves as an inhibitor of DJ-1 , or wherein an decrease in the suppressor function of said Tregs compared to said Tregs before contacting indicates that the nucleic acid molecule, preferably a siRNA or a miRNA, the binding protein, the small molecule or the compound of interest serves as an activator of DJ-1 .

[009] Additionally, the present invention relates to a method for determining whether or not a cell is susceptible to the treatment with an inhibitor as described herein, comprising determining whether or not said cell expresses DJ-1 .

[010] Also, the present invention relates to a kit comprising an inhibitor of DJ-1 as described herein.

[011] Further, the present invention relates to an inhibitor of DJ-1 (PARK7) for use in treating or preventing of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer, wherein the treating or preventing comprises

(i) contacting Tregs and/or Teffs with the inhibitor.

[012] The present invention also relates to an inhibitor of DJ-1 (PARK7) for use in treating or preventing of one or more of autoimmune disease, allergy or infectious disease, wherein the treating or preventing comprises

(i) contacting Tregs and/or Teffs with the inhibitor.

[013] In addition, the present invention relates to an inhibitor of DJ-1 (PARK7) for use in treating or preventing of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer, wherein the treating or preventing comprises

(i) obtaining Tregs and/or Teffs from a subject;

(ii) contacting said Tregs and/or Teffs with the inhibitor, and

(iii) re-introducing said Tregs and/or Teffs to the subject.

[014] The present invention also relates to an inhibitor of DJ-1 (PARK7) for use in treating or preventing of one or more of autoimmune disease, allergy or infectious disease, wherein the treating or preventing comprises

(i) obtaining Tregs and/or Teffs from a subject;

(ii) contacting said Tregs and/or Teffs with the inhibitor, and

(iii) re-introducing said Tregs and/or Teffs to the subject.

[015] Furthermore, the present invention relates to a method of treating of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer, the method comprising

(i) administering a therapeutically effective amount of an inhibitor of DJ-1 (PARK7) to the subject.

[016] The present invention also relates to a method of treating of one or more of autoimmune disease, allergy or infectious disease, the method comprising

[017] Additionally, the present invention relates to a use of an inhibitor as described herein, for the preparation of a medicament for the treatment of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer. The present invention also relates to a use of an inhibitor as described herein, for the preparation of a medicament for the treatment of one or more of autoimmune disease, allergy or infectious disease.

[018] The figures show

[019] Figure 1 : DJ-1 protein is also highly expressed in both human Tregs and Teffs. In the upper panel, DJ-1 expression in Treg and Teffs was assessed by Western blotting. In the lower panel, DJ-1 expression in Tregs was assessed by FACS (left), the Cp value of DJ-1 and RPS9 in Tregs stimulated by two days measured by realtime PCR (right).

[020] Figure 2: Network analysis strategy shows that DJ-1 (PARK7) is connected with well known Treg key players.

[021] Figure 3: DJ-1/PARK/ knockdown rescues Treg suppressor function in FoxP3 deficient Tregs. Upper panel: The CFSE dilution measurement of the Teff proliferation co-cultured with Tregs at various ratios of Tregs treated with si_NS (or with specific siRNA against PAKR7 or against FOXP3 or against both FOXP3 and PARK7) to Teffs as well as co-cultured EBV-B cells after 4 days. Number in each histogram represents the geometric mean of fluorescence intensity of CFSE (the total population indicates the gated DAPI-negative and CD4+, CFSE stained Teffs). Results are representative of four independent experiments. Lower panel: schematic representation of the upper figure.

[022] Figure 4: DJ-1 rescues the suppressive function of FOXP3-silenced Tregs via regulating the expression of Treg key genes and cytokines. Left: mRNA expression of FOXP3, PLAU, GARP and CTLA4 measured by realtime PCR in Tregs treated with various specific siRNA. The numbers on the y-axis indicate fold changes relative to RPS9. Error bars represent standard deviation (SD) values. The P-values indicate the results from a two-tailed Student's t-test for three repeated measurements. P<=0.05, is indicated by ^*; P<=0.01 , by ^**; P<=0.001 , by^*** for all the figures. Before performing the qPCR experiments, we first transfected Tregs with siRNA for one day followed by 2-day stimulation of anti-CD3/-CD28 beads with IL2. Data represent two independent experiments. Right: mRNA expression of PAKR7, IL4, IL5 and IL13 measured by realtime PCR in Tregs treated with various specific siRNA. Before performing the qPCR experiments, we first transfected Tregs with siRNA for one day followed by a two-day stimulation of anti-CD3/-CD28 beads with IL2. For the PARK7 gene, we analyzed it after 1 day stimulation.

[023] Figure 5: DJ-1 regulates ROS levels in Tregs and ROS mediates FOXP3 and CTLA4 expression. Left: Mitochondrial ROS was measured by the molecular probes MitoSOX. Tregs transfected with nonspecific siRNA or DJ-1/PARK7 specific siRNA were rested for 1 day before being restimulated by anti-CD3/-CD28 beads with IL2. Enlarged numbers indicate the geometric mean of fluorescence intensity of MitoSOX. 'Max', maximum. Right: The ROS inhibitor DPI decreases FOXP3 and CTLA4 expression in the stimulated Tregs. In the top panel, principle of the DPI-treatment experimental design. mRNA expression levels of FOXP3, CTLA4 and LGMN at different time points following beads/IL2 stimulation after treated with a gradient concentration of DPI. The numbers on the y-axis indicate fold changes relative to RPS9. Error bars represent standard deviation (SD) values. The P-values indicate the results from a two-tailed Student's t-test for three repeated measurements.

[024] Figure 6: Knockdown of DJ-1 mediates Treg suppressor function via regulating cell cycle and TCR signaling pathways. mRNA expression analysis ("Heatmap"), see Examples for details.

[025] Figure 7: DJ-1/PARK7 controls the down-regulated genes via NUPR1 , PIAS1 , CD24, TCR and EP400 in Tregs. Ingenuity Pathway Analysis (IPA) of DJ-1/PARK7 expression dependent transcriptomics data.

[026] Figure 8: Co-lmmunoprecipitation (Co-IP) experiments of DJ-1/PARK7 in different cellular contexts. Co-IP analysis following standard Co-IP routines. See Examples for details.

[027] CD4+ Regulatory T cells (Tregs) not only play a vital role in suppressing autoimmunity and maintaining immune homeostasis at the periphery as shown in autoimmune diseases, infectious diseases, cancer and others(Belkaid et al. (200/), Sakaguchi et al. (2010); Huehn et al. (2009); Josefowitcz et al. (2012)), but also potentially contribute to self-tolerance and immune privilege in the central nervous system(He et al. (2013); Schwartz and Baruch (2014)). Using a network strategy we have predicted the known neurodegenerative disease gene DJ-1 to play a role in Tregs.

[028] Following the prediction of a network analysis, DJ-1 as been surprisingly found to negatively mediate human natural Treg (nTreg) suppressor function. Remarkably, a dual-knockdown of DJ-1 and FOXP3 rescues the suppressive function of FOXP3- deficient nTregs by rebounding FOXP3 and CTLA4 expression in FOXP3-deficient nTregs. Furthermore, knockdown of DJ-1 significantly upregulates mitochondrial ROS (Reactive Oxygen Species) levels in nTregs and inhibiting ROS reverses the effects of DJ-1 knockdown. Surprisingly, a transcriptome analysis shows that a knock-down of DJ-1 strengthens Treg suppressor capability by suppressing TCR signalling pathway and promoting S-phase arrest of FOXP3-deficient nTregs. Co- immunoprecipiation analysis shows that DJ-1 preferentially binds to granyzme B and a known DJ-1 binding partner DAXX as well as some other binding partners in stimulated but not resting Tregs. Inversely, DJ-1 specifically binds with some proteins only in resting but not stimulated Tregs, e.g., the gelectin-3-binding protein and an anti-inflammatory gene annexin A1 . Interestingly, these bindings happen only in Tregs but not in effector CD4+ T cells, indicating that the well-known PD gene DJ-1 plays an important novel regulatory role in Tregs.

[029] The present invention relates to an inhibitor of protein deglycase DJ-1 (PARK7) (abbreviated as DJ-1 herein) for use in the treatment or prevention of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer. It is also envisioned by the present invention that the cancer is not lung or breast cancer.

[030] In general a "therapy" or "treatment" seeks remediation of a health problem such as cancer, usually following a diagnosis. In the medical field, this term is synonymous with treatment of a disease or disorder. Therefore, in this context, a therapy also includes the administration of an inhibitor of DJ-1 . Likewise, a "therapeutic effect" relieves to some extent one or more of the symptoms of the abnormal condition, such as autoimmune disease, allergy, infectious disease or cancer.

[031] The present invention contemplates any inhibitors that can serve as an inhibitor of DJ-1 . The determination of whether or not a substance of interest e.g. a siRNA, a miRNA, a binding protein, a small molecule or a compound of interest is an inhibitor of DJ-1 is within the skill of one of ordinary skill in the art. Examples of assays useful to identify inhibitor of DJ-1 include those as described in the Examples.

[032] An example of how one could determine if a compound is an inhibitor of DJ-1 would be to isolate the DJ-1 protein. For example, the amino acid sequence of the protein that encodes human DJ-1 can have or comprise uniprot number Q99497 (SEQ ID NO: 17). The amino acid sequence of the protein that encodes mouse DJ-1 can have or comprise uniprot number Q99LX0 (version 1 , last modified June 1 , 2001 ) that encodes DJ-1 in chicken (Gallus gallus) can have or comprise uniprot number Q8UW59 (version 1 , last modified March 1 , 2002), that encodes DJ-1 in rat can have or comprise uniprot number 088767 (version 1 , last modified November 1 , 1998).

[033] The protein can be isolated from cells where the DJ-1 is naturally expressed or where it has been overexpressed by means of transfection of a genetic construct or infection with a virus that directs the expression of the DJ-1 . The nucleic acid sequence of mRNA that encodes DJ-1 can have or comprise NCBI Reference Sequence: N J307262.4 (SEQ ID NO: 18) or NM_001 123377.1 (SEQ ID NO. 19). Also mRNA can be isolated from a cell and e.g. be expressed in a host cell. DJ-1 can for example be expressed recombinantly.

[034] An inhibitor to DJ-1 may be effective in any possible way. For example, the expression of DJ-1 (e.g. of DJ-1 protein, mRNA or even transcription of DNA) may be inhibited/reduced. Another possibility can be that the function of DJ-1 may be inhibited/reduced/decreased.

[035] In general any reduction in expression as described herein can be measured by any technique, which is known to the skilled person. For example, such measurement can be performed by "real-time PGR" or "Real-time Polymerase Chain Reaction (RT-PCR)" or qPCR. This technique has the ability to monitor the progress of the PGR as it occurs (i.e., in real time). Data is therefore collected throughout the PGR process, rather than at the end of the PGR. In real-time PGR, reactions are characterized by the point in time during cycling when amplification of a target is first detected rather than the amount of target accumulated after a fixed number of cycles. There are two main methods used to perform quantitative PGR: dye-based and probe-based detection. Both methods rely on calculating the initial (zero cycle) DNA concentration by extrapolating back from a reliable fluorescent signal. The basic principle of this method is known in the art (Arya M, Shergill I S, Williamson M, Gommersall L, Arya N, Patel HRH "Basic principles of quantitative real time PGR" Expert Rev. Mol. Diagn. 5(2):209-219).

[036] An inhibitor of DJ-1 can thus descrease the expression of an amino acid sequence or nucleic acid molecule comprising SEQ ID NO. 17, SEQ ID NO. 18 and/or SEQ ID NO. 19 or an amino acid sequence or nucleic acid molecule having at least 60 %, 70 %, 80 % 90 % 95 % 99 % sequence identity to any of SEQ ID No. 17, 18 and/or 19 e.g. in a cell compared to a control or compared to the expression before the addition of the inhibitor.

[037] An inhibitor may additionally or alternatively inhibit/reduce/decrease DJ-1 (function) by 10 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 % or more when compared to the activity of DJ-1 without the addition of the inhibitor or compared to the acitivty of DJ-1 before the addition of the inhibitor. A block of DJ-1 (function) to be inhibited is present when the enzymatic activity of DJ-1 is inhibited by 100 % when compared to the enzymatic activity of DJ-1 without the addition of the inhibitor or compared to the activty of DJ-1 before the addition of the inhinitor.

[038] Upon isolating the DJ-1 protein a person of ordinary skill in the art can measure its activity in the presence or absence of a potential DJ-1 inhibitor, preferably using positive and/or negative controls. Notably, DJ-1 under an oxidative condition can inhibit the aggregation of a-synuclein via its chaperone activity, thus can function as a redox-sensitive chaperone and as a sensor for oxidative stress. Accordingly, DJ-1 can protect neurons against oxidative stress and cell death. Additionally or alternatively, DJ-1 protein can act as a positive regulator of androgen receptor-dependent transcription. Additionally or alternatively, as described in the Examples herein a DJ-1 inhibitor can also enhance Treg suppressor function. Notably, Tregs can be immunosuppressive and can suppress or downregulate induction and proliferation of effector T cells.

[039] Therefore, if the activity of DJ-1 is less in the presence of the inhibitor than in the absence of an alleged inhibitor, then this inhibitor truly is an DJ-1 inhibitor. For example, an assay comprising an inhibitor of DJ-1 may generate more aggegration of a-synuclein and/or increase neuronal death and/or enhance Treg suppressor function in Treg cells than the same assay/Treg cell without the inhibitor. Then the inhibitor decreases DJ-1 function.

[040] To confirm that an molecule of interest/compound/small molecule/binding protein as decribed herein truly is a DJ-1 inhibitor useful to treat one or more of autoimmune disease, allergy, infectious disease or cancer, the inhibitor may be tested in a routine immune cell such as effector T cell proliferation assay to confirm and assess its activity to reduce proliferation of effector T cells.

[041] The present invention further contemplates that the DJ-1 inhibitor can suppress or downregulate proliferation of effector T cells of around 5 %, 10 %, 15 %, 20 % 25 %, 30 %, 35 %, 40 %, 45 %, 50 % or more compared to the proliferation/growth measured before addition of the inhibitor(s). The inhibitors for use of the present invention can for example be a siRNA, miRNA, binding protein, small molecule or compound. Exemplary binding proteins include an antibody, a divalent antibody fragment, a monovalent antibody fragment, or a proteinaceous binding molecule with antibody-like binding properties.

[042] Such an "antibody" can e.g. be a full length antibody, a recombinant antibody molecule, or a fully human antibody molecule. A full length antibody can be any naturally occurring antibody. The term "antibody" also can include immunoglobulins (Ig's) of different classes (i.e. IgA, IgG, IgM, IgD and IgE) and subclasses (such as lgG1 , lgG2 etc.). Such full length antibodies can be isolated from different animals such as e.g. different mammalian species. The "recombinant antibody molecule" refers to an antibody molecule, the genes of which have been cloned, and is produced recombinantly in a host cell or organism, using well-known methodologies of genetic engineering. Typically, a recombinant antibody molecule has been genetically altered to comprise an amino acid sequence, which is not found in nature. Thus, a recombinant antibody molecule can be a chimeric antibody molecule or a humanized antibody molecule.

[043] The antibody/inhibitor can also be an "antibody fragment". Such antibody fragments comprise any part of an antibody, which comprises a binding site. Illustrative examples of such an antibody fragment are single chain variable fragments (scFv), Fv fragments, single domain antibodies, such as e.g. VHH (camelid) antibodies, di-scFvs, fragment antigen binding regions (Fab), F(ab')2 fragments, Fab' fragments, diabodies or domain antibodies, to name only a few (Holt LJ, Herring C, Jespers LS, Woolven BP, Tomlinson IM. Domain antibodies: proteins for therapy. Trends Biotechnol. 2003 Nov; 21 (1 1 ):484-90).

[044] For example, an inhibitor/antibody used in the present invention can be a divalent antibody fragment such as an (Fab)2'-fragment or a divalent single-chain Fv fragment. Therefore, an antibody/inhibitor used in the present invention can be an antibody or antibody fragment, which has an antibody format as described in International patent application WO2013/092001 . Alternatively, the inhibitor/antibody might also be a bivalent proteinaceous artificial binding molecule such as a lipocalin mutein that is also known as "duocalin".

[045] An inhibitor or an antibody used in the present invention may only have a single binding site, i.e., may be monovalent. Examples of monovalent inhibitors include, but are not limited to, a monovalent antibody or antibody fragment, a monovalent proteinaceous binding molecule with antibody-like binding properties. Examples of monovalent antibody fragments include, but are not limited to a Fab fragment, a Fv fragment, and a single-chain Fv fragment (scFv).

[046] In some embodiments, antibody derived inhibitors that are used in the present invention may comprise an attenuated Fc-part. An Fc-part is, for example, attenuated, when such an antibody molecule is not able to bind via the CH2 or the CH3 domain to Fc receptors anymore, or binds less efficiently to them than a parent antibody. Examples of mutations that can be introduced into the CH2 or CH3 domain to achieve such Fc attenuation are described in International patent application WO2013/092001 (cf. for example, Figures 1 N, O of WO 2013/092001 ). In other embodiments, antibody derived inhibitors used in the present invention may comprise no Fc part at all.

[047] The binding protein as used in the present invention can thus be selected from the group consisting of an (full length, recombinant, chimeric) antibody, a divalent antibody fragment, a monovalent antibody fragment, or a proteinaceous binding molecule with antibody-like binding properties.

[048] The present invention envisiones that the divalent antibody fragment can be an (Fab)2'-fragment, a divalent single-chain Fv fragment, a bsFc-1/2-dimer or a bsFc- CH3-1/2 dimer.

[049] It is also contemplated by the present invention that the monovalent antibody fragment is selected from the group consisting of a Fab fragment, a Fv fragment, a single-chain Fv fragment (scFv) or an scFv-Fc fragment.

[050] An inhibitor used in the present invention can also be a proteinaceous binding molecule with antibody-like binding properties. Non-limiting examples of a proteinaceous binding molecule with antibody-like binding properties inlcude an aptamer, a mutein based on a polypeptide of the lipocalin family, a glubody, a protein based on the ankyrin scaffold, a protein based on the crystalline scaffold, an adnectin, an avimer or a (recombinant) receptor protein.

[051] Further illustrative examples of proteinaceous binding molecules with antibody-like binding properties that can be used as inhibitor include, but are not limited to, a EGF-like domain, a Kringle-domain, a fibronectin type I domain, a fibronectin type II domain, a fibronectin type III domain, a PAN domain, a G1 a domain, a SRCR domain, a Kunitz/Bovine pancreatic trypsin Inhibitor domain, tendamistat, a Kazal-type serine protease inhibitor domain, a Trefoil (P-type) domain, a von Willebrand factor type C domain, an Anaphylatoxin-like domain, a CUB domain, a thyroglobulin type I repeat, LDL-receptor class A domain, a Sushi domain, a Link domain, a Thrombospondin type I domain, a C-type lectin domain, a MAM domain, a von Willebrand factor type A domain, a Somatomedin B domain, a WAP- type four disulfide core domain, a F5/8 type C domain, a Hemopexin domain, an SH2 domain, an SH3 domain, a Laminin-type EGF-like domain, a C2 domain, "Kappabodies" (III CR1 , Gonzales JN, Houtz EK, Ludwig JR, Melcher ED, Hale JE, Pourmand R, Keivens VM, Myers L, Beidler K, Stuart P, Cheng S, Radhakrishnan R. Design and construction of a hybrid immunoglobulin domain with properties of both heavy and light chain variable regions. Protein Eng. 1997 Aug;10(8):949-57) "Minibodies" (Martin F, Toniatti C, Salvati AL, Venturini S, Ciliberto G, Cortese R, Sollazzo M. The affinity-selection of a minibody polypeptide inhibitor of human interleukin-6. EMBO J. 1994 Nov 15;13(22):5303-9), "Janusins" (Traunecker A, Lanzavecchia A, Karjalainen K. Bispecific single chain molecules (Janusins) target cytotoxic lymphocytes on HIV infected cells. EMBO J. 1991 Dec;10(12):3655-9 and Traunecker A, Lanzavecchia A, Karjalainen K. Janusin: new molecular design for bispecific reagents. Int J Cancer Suppl. 1992;7:51 -2), a nanobody, a tetranectin, a microbody, an affilin, an affibody or an ankyrin, a crystallin, a knottin, ubiquitin, a zinc- finger protein, an autofluorescent protein, an ankyrin or ankyrin repeat protein or a leucine-rich repeat protein, an avimer (Silverman J, Liu Q, Bakker A, To W, Duguay A, Alba BM, Smith R, Rivas A, Li P, Le H, Whitehorn E, Moore KW, Swimmer C, Perlroth V, Vogt M, Kolkman J, Stemmer WP. Multivalent avimer proteins evolved by exon shuffling of a family of human receptor domains. Nat Biotechnol. 2005 Dec;23(12):1556-61 ); as well as multivalent avimer proteins evolved by exon shuffling of a family of human receptor domains as also described in Silverman et al. (2005) cited herein). In some embodiments, the inhibitor used in the present invention is a proteinaceous binding molecule with antibody-like binding properties, which is selected from the group of an aptamer, a mutein based on a polypeptide of the lipocalin family, a glubody, a protein based on the ankyrin scaffold, a protein based on the crystalline scaffold, an adnectin, and an avimer.

[052] Alternatively, an inhibitor used in the present invention can also be a non- proteinaceous aptamer. Such an aptamer is an oligonucleic acid that binds to a specific target molecule. These aptamers are usually created by selecting them from a large random sequence pool, but natural aptamers also exist. More specifically, aptamers can be classified as: DNA or RNA aptamers. They consist of (usually short) strands of oligonucleotides. Therefore, a proteinaceous aptamer as described above may also include an oligonucleotide portion in addition to a protein portion.

[053] The inhibitors for use of the present invention can also be a small molecule. Such a small molecule can have a low molecular weight of less than 900 daltons (da), less than 800 da, less than 700 da, less than 600 da or less than 500 da. The size of a small molecule can be determined by methods well-known in the art, e.g., mass spectrometry.

[054] The inhibitor for use of the present invention can also be a compound or compound of interest. The term "compound" embraces any compound that may serve as an inhibitor for DJ-1 as described herein. Such a compound, as also the small molecule, antibody, miRNA or siRNA or any other inhibitor as described herein, may be detected by the screening methods as described herein. If a coumpound/inhibitor is in inhibitor or activator of DJ-1 can also be analyzed as described herein. One possibility is to measure DJ-1 expression before and after addition of the compound/molecule of interest.

[055] For exampe, methods by which one can elucidate the structure of a compound includes spectroscopies such as nuclear magnetic resonance (proton and carbon-13 NMR), various methods of mass spectrometry (to give overall molecular mass, as well as fragment masses), and x-ray crystallography. Techniques such as absorption spectroscopy and the vibrational spectroscopies, infrared and Raman, can provide, respectively, important supporting information about the numbers and adjacencies of multiple bonds, and about the types of functional groups (whose internal bonding gives vibrational signatures); further inferential studies that give insight into the contributing electronic structure of molecules include cyclic voltammetry and X-ray photoelectron spectroscopy.

[056] The inhibitors for use of the present invention can also be a nucleic acid molecule such as siRNA or miRNA.

[057] The term "nucleic acid molecule" when used herein encompasses any nucleic acid molecule having a nucleotide sequence of bases comprising purine- and pyrimidine bases which are comprised by said nucleic acid molecule, whereby said bases represent the primary structure of a nucleic acid molecule. Nucleic acid sequences can include DNA, cDNA, genomic DNA, RNA, both sense and antisense strands, or may contain non-natural or derivatized nucleotide bases, as will be readily appreciated by those skilled in the art. A polynucleotide can be composed of any polyribonucleotide or polydeoxribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA.

[058] A variety of modifications can be made to DNA and RNA; thus, the term "nucleic acid molecules" can embrace chemically, enzymatically, or metabolically modified forms. "Modified" bases include, for example, tritylated bases and unusual bases such as inosine.

[059] The nucleic acid molecule can, for example, be a siRNA or a miRNA. Further, the nucleic acid molecule can, for example, be designed with regard to a target sequence. The target sequence can, for example, be a nucleic acid molecule of any of SEQ ID NO. 18 and/or 19. The nucleic acid molecule that can be used in the present invention can therefore comprise a sequence that is complementary to a sequence that comprises any of SEQ ID NO: 18 and/or 19. The present invention also encompasses nucleic acid sequences (in particular siRNA sequences) which are 50 %, 60 %, 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % complementary to a nucleic acid molecule that comprises a sequence of SEQ ID NO: 18 and/or 19.

[060] The terms "complementary" or "complementarity" refer to the natural binding of polynucleotides under permissive salt and temperature conditions by base-pairing. For example, the sequence "A-G-T" binds to the complementary sequence "T-C-A". Complementarity between two single-stranded molecules may be "partial", in which only some of the nucleic acids bind, or it may be complete when total complementarity exists between single-stranded molecules.

[061] The inhibitor of DJ-1 for use in the present invention can for example be a nucleic acid molecule such as a siRNA that has a sequence identity of at least 50 %, 60%, 70%, 80%, 90%, 95%, 98% 99% or 100% to SEQ ID NO: 1 .

[062] In accordance with the present invention, the term "identical" or "percent identity" in the context of two or more nucleic acid or amino acid sequences, refers to two or more sequences or subsequences that are the same, or that have a specified percentage of amino acid residues or nucleotides that are the same (e.g., 60% or 65% identity, preferably, 70-95% identity, more preferably at least 95% identity), when compared and aligned for maximum correspondence over a window of comparison, or over a designated region as measured using a sequence comparison algorithm as known in the art, or by manual alignment and visual inspection. Sequences having, for example, 60% to 95% or greater sequence identity are considered to be substantially identical. Such a definition also applies to the complement of a test sequence. Preferably the described identity exists over a region that is at least about 15 to 25 amino acids or nucleotides in length, more preferably, over a region that is about 50 to 100 amino acids or nucleotides in length. Those having skill in the art will know how to determine percent identity between/among sequences using, for example, algorithms such as those based on CLUSTALW computer program (Thompson Nucl. Acids Res. 2 (1994), 4673-4680) or FASTDB (Brutlag Comp. App. Biosci. 6 (1990), 237-245), as known in the art.

[063] Although the FASTDB algorithm typically does not consider internal non- matching deletions or additions in sequences, i.e., gaps, in its calculation, this can be corrected manually to avoid an overestimation of the % identity. CLUSTALW, however, does take sequence gaps into account in its identity calculations. Also available to those having skill in this art are the BLAST and BLAST 2.0 algorithms (Altschul Nucl. Acids Res. 25 (1977), 3389-3402). The BLASTN program for nucleic acid sequences uses as defaults a word length (W) of 1 1 , an expectation (E) of 10, M=5, N=4, and a comparison of both strands.

[064] In general, all the inhibitors mentioned herein can also be such that they hybridize to the DJ-1 mRNA that can be translated to the protein sequences as described herein. For example, such mRNA may be translated into a protein comprising amino acid sequence of SEQ ID NO. 17. Furthermore, the inhibitor may hybridize to a sequence comprising a nucleic acid sequence of SEQ ID NO. 18 and/or SEQ ID NO. 19.

[065] The term "hybridizes" as used in accordance with the present invention may relate to hybridizations under stringent or non-stringent conditions. If not further specified, the conditions are preferably non-stringent. Said hybridization conditions may be established according to conventional protocols described, for example, in Sambrook, Russell "Molecular Cloning, A Laboratory Manual", Cold Spring Harbor Laboratory, N.Y. (2001 ); Ausubel, "Current Protocols in Molecular Biology", Green Publishing Associates and Wiley Interscience, N.Y. (1989), or Higgins and Hames (Eds.) "Nucleic acid hybridization, a practical approach" IRL Press Oxford, Washington DC, (1985). The setting of conditions is well known within the skill of the artisan and can be determined according to protocols described in the art. Thus, the detection of only specifically hybridizing sequences will usually require stringent hybridization and washing conditions such as O.lxSSC, 0.1 % SDS at 65°C. Non- stringent hybridization conditions for the detection of homologous or not exactly complementary sequences may be set at 6xSSC, 1 % SDS at 65°C. As is well known, the length of the probe and the composition of the nucleic acid to be determined constitute further parameters of the hybridization conditions. Notably variations in the above conditions may be accomplished through the inclusion and/or substitution of alternate blocking reagents used to suppress background in hybridization experiments. Typical blocking reagents include Denhardt's reagent, BLOTTO, heparin, denatured salmon sperm DNA, and commercially available proprietary formulations. The inclusion of specific blocking reagents may require modification of the hybridization conditions described above, due to problems with compatibility.

[066] Additionally, a hybridization complex refers to a complex between two nucleic acid sequences by virtue of the formation of hydrogen bonds between complementary G and C bases and between complementary A and T bases; these hydrogen bonds may be further stabilized by base stacking interactions. The two complementary nucleic acid sequences hydrogen bond in an antiparallel configuration. A hybridization complex may be formed in solution (e.g., Cot or Rot analysis) or between one nucleic acid sequence present in solution and another nucleic acid sequence immobilized on a solid support (e.g., membranes, filters, chips, pins or glass slides to which, e.g., cells have been fixed).

[067] In addition, the inhibitors can be a nucleic acid sequence that is 50 %, 60 %, 70 %, 80 %, 90 %, 95 %, 99 % or 100 % complementary to a mRNA that will be translated into an amino acid sequence comprising SEQ ID No. 17 or comprising an amino acid sequence having a sequence identity of 50 %, 60 %, 70 %, 80 %, 90 %, 95 %, 99 % or 100 % to any of SEQ ID NO. 17 or to the nucleic acid sequence compising SEQ ID NO. 18 and/or SEQ ID NO. 19 or a nucleic acid sequence having a sequence identity of 50 %, 60 %, 70 %, 80 %, 90 %, 95 %, 99 % or 100 % to SEQ ID NO. 18 and/or 19.

[068] The present invention also contemplates that the inhibitor for use such as the nucleic acid molecule like siRNA or miRNA are provided within a plasmid vector and/or are modified or encapsulated by synthetic or natural nanoparticles. The synthetic or natural lipid nanoparticles may for example comprise lipids as well as polymers and/or metals.

[069] It is also envisioned by the present invention that the nanoparticle comprises one or more of natural or synthetic lipids (e.g., liposomes, micelles), polymers (e.g, chitosan, poly(lactic-co-glycolic) acid (PLGA), polylactic acid (PLA), polyethilenimine (PEI), atelocollagen), carbon nanotubes, quantum dots, gold nanoshells or iron oxide magnetic. The nanoparticle can additionally or alternatively be biodegradable.

[070] For example, the nanoparticle can be a liposomal nanoparticle. Exemplary liposomal nanoparticles include, but are not limited to cationic-lipid based liposome, neutral lipid-based nanoliposome, a solid lipid-based systems (SNALP and SLN) or lipidoid nanoparticle.

[071] The present invention further contemplates that the inhibitor for the use in the invention can decrease expression of DJ-1 in unstimulated or stimulated T effector cells (Teffs) and/or unstimulated or stimulated regulatory T cells (Tregs), preferably the Teff is a human Teff and the Treg is a human Treg.

[072] For example, the Treg can be a human natural Treg (nTreg) and/or a Treg with impaired suppressor function.

[073] Additionally or alternatively, the inhibitor for use in the invention can increase Treg suppressor function.

[074] Additionally or alternatively, the inhibitor for use in the invention can increase Treg suppressor function in a Treg compared to the Treg before it has been contacted with the inhibitor. For example, the inhibitor increases Treg suppressor function at high ratios such as ratios of 1 :4 or 1 :8 (Treg:Teff ratios). Additionally or alternatively, the inhibitor does not increase Treg suppressor function at low ratios (Treg eff ratios).

[075] Additionally or alternatively, the inhibitor for use in the invention can increase Treg suppressive function of Tregs with an impaired suppressor function. The Treg with an impaired suppressor function can for example be a Treg that has been obtained from a subject having an autoimmune disease, allergy, infectious disease or cancer. Additionally or alternatively, the Treg with an impaired suppressor function can be a Treg having a FOXP3 deficiency.

[076] Additionally or alternatively, the inhibitor for use in the invention can up- regulate one or more genes in the Treg with an impaired suppressor function. This means that the expression of these genes is increased. Expression of a gene can include expression of the protein or mRNA, which are translated/transcribed from the gene.

[077] For example, the one or more genes can be selected from the group consisting of FOXP3 (forkhead box P3), GARP (Leucine-Rich Repeat-Containing Protein 32), CTLA4 (cytotoxic T-lymphocyte-associated protein 4) or EOS (IKZF4; IKAROS Family Zinc Finger 4).

[078] "FOXP3" as used herein can mean any forkhead box P3. For example, FOXP3 may comprise or have the sequence of SEQ ID NO. 20 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 20. FOXP3 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 20, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 20.

[079] "GARP" as used herein can mean any Leucine-Rich Repeat-Containing Protein 32. For example, GARP may comprise or have the sequence of SEQ ID NO.

21 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 21 . GARP can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 21 , and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 21 .

[080] "CTLA4" as used herein can mean any cytotoxic T-lymphocyte-associated protein 4. For example, CTLA4 may comprise or have the sequence of SEQ ID NO.

22 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 22. CTLA4 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 22, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 22.

[081] "EOS" as used herein can mean any cytotoxic T-lymphocyte-associated protein 4. For example, EOS may comprise or have the sequence of SEQ ID NO. 23 or be a sequence, which is 70 %, 80 %, 85 %, 90%, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 23. EOS can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 23, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 23.

[082] Additionally or alternatively, the inhibitor for use in the invention can increase the reactive oxygen species (ROS) burst level in Tregs, preferably nTregs. For example, the ROS can be selected from the group consisting of peroxides, superoxides, hydroxyl radicals, or singlet oxygen.

[083] Additionally or alternatively, the inhibitor for use in the invention can decrease the expression of UBE1 (E1 ubiquitin-activating enzyme), E2 ubiquitin-conjugating enzymes such as UBE2D3 and UBE2O and/or SKP2 (S-phase kinase-associated protein 2).

[084] "UBE1 " as used herein can mean any E1 ubiquitin-activating enzyme. For example, UBE1 may comprise or have the sequence of SEQ ID NO. 24 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 24. UBE1 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 24, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 24.

[085] "UBE2D3" as used herein can mean any E2 ubiquitin-conjugating enzyme UBE2E3. For example, UBE2E3 may comprise or have the sequence of SEQ ID NO.

25 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 25. UBE2D3 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 25, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 25.

[086] "UBE2O" as used herein can mean any E2 ubiquitin-conjugating enzyme UBE2O. For example, UBE2O may comprise or have the sequence of SEQ ID NO.

26 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 26. UBE2O can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 26, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 26.

[087] "SPK2" as used herein can mean any S-phase kinase-associated protein. For example, SPK2 may comprise or have the sequence of SEQ ID NO. 27 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 27. SPK2 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 27, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 27.

[088] The term "expression" when used herein means the expression on the DNA, mRNA and/or protein level.

[089] Additionally or alternatively, the inhibitor for use in the invention can increase the expression of E3 ubiquitin-ligases such as UBE4B (Ubiquitin conjugation factor E4 B), TRIP12 (Thyroid Hormone Receptor Interactor 12) and/or SMURF2 (SMAD Specific E3 Ubiquitin Protein Ligase 2). [090] "UBE4B" as used herein can mean any S Ubiquitin conjugation factor E4 B. For example, UBE4B may comprise or have the sequence of SEQ ID NO. 28 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 28. UBE4B can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 28, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 28.

[091] "TRIP12" as used herein can mean any Thyroid Hormone Receptor Interactor 12. For example, TRIP12 may comprise or have the sequence of SEQ ID NO. 29 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 29. TRIP12 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 29, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 29.

[092] "SMURF2" as used herein can mean any SMAD Specific E3 Ubiquitin Protein Ligase 2. For example, SMURF2 may comprise or have the sequence of SEQ ID NO. 30 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 30. SMURF2 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 30, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 30.

[093] Additionally or alternatively, the inhibitor for use in the invention can decrease the interaction of DJ-1 with GZMB (Granzyme B).

[094] "GZMB" as used herein can mean any Granzyme B. For example, GZMB may comprise or have the sequence of SEQ ID NO. 31 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 31 . GZMB can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 31 , and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 31 .

[095] Additionally or alternatively, the inhibitor for use in the invention can decrease the interaction of DJ-1 with UPF1 (Regulator of nonsense transcripts 1 ), PPP1 CB (Serine/threonine-protein phosphatase PP1 -beta catalytic subunit), ATP5D (ATP synthase subunit delta, mitochondrial), EIF2A (Eukaryotic translation initiation factor 2A), EIF5B (Eukaryotic translation initiation factor 5B), MAP4K1 (Mitogen-activated protein kinase 1 ) and/or ANXA4 (Annexin IV) in stimulated Tregs.

[096] "UPF1 " as used herein can mean any Regulator of nonsense transcripts 1 . For example, UPF1 may comprise or have the sequence of SEQ ID NO. 32 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 32. UPF1 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 32, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 % 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 32.

[097] "PPP1 CB" as used herein can mean any Serine/threonine-protein phosphatase PP1 -beta catalytic subunit. For example, PPP1 CB may comprise or have the sequence of SEQ ID NO. 33 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 33. PPP1 CB can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 33, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 33.

[098] "ATP5D" as used herein can mean any mitochondrial ATP synthase subunit delta. For example, ATP5D may comprise or have the sequence of SEQ ID NO. 34 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 34. ATP5D can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 34, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 34.

[099] "EIF2A" as used herein can mean any Eukaryotic translation initiation factor 2A. For example, EIF2A may comprise or have the sequence of SEQ ID NO. 35 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 35. EIF2A can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 35, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 35.

[100] "EIF5B" as used herein can mean any Eukaryotic translation initiation factor 5B. For example, EIF5B may comprise or have the sequence of SEQ ID NO. 36 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 36. EIF5B can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 36, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 36.

[101] "MAP4K1 " as used herein can mean any Mitogen-activated protein kinase 1 . For example, MAP4K1 may comprise or have the sequence of SEQ ID NO. 37 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 37. MAP4K1 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 37, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 37.

[102] "ANXA4" as used herein can mean any Annexin IV. For example, ANXA4 may comprise or have the sequence of SEQ ID NO. 38 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 38. ANXA4 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 38, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 % 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 38.

[103] Additionally or alternatively, the inhibitor for use in the invention can decrease the interaction of DJ-1 with LGALS3BP (Galectin-3-binding protein), MOV10 (RISC complex RNA helicase) and/or PDHB (pyruvate dehydrogenase (lipoamide) beta) in unstimulated Tregs.

[104] "LGALS3BP" as used herein can mean any Galectin-3-binding protein. For example, LGALS3BP may comprise or have the sequence of SEQ ID NO. 39 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 39. LGALS3BP can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 39, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 39.

[105] "MOV10" as used herein can mean any RISC complex RNA helicase. For example, MOV10 may comprise or have the sequence of SEQ ID NO. 40 or be a sequence, which is 70 %, 80 %, 85 %, 90%, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 40. MOV10 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 40, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 40.

[106] "PDHB" as used herein can mean any pyruvate dehydrogenase (lipoamide) beta. For example, PDHB may comprise or have the sequence of SEQ ID NO. 41 or be a sequence, which is 70 %, 80 %, 85 %, 90%, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 41 . PDHB can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 41 , and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 41 .

[107] Additionally or alternatively, the inhibitor for use in the invention can decrease the interaction of DJ-1 with PPFIA1 (Protein Tyrosine Phosphatase Receptor Type F Polypeptide-lnteracting Protein Alpha-1 ), CHMP4B (Charged Multivesicular Body Protein 4B), CLIC1 (Chloride Intracellular Channel 1 ), RARA (Retinoic Acid Receptor, Alpha), MATR3 (Matrin 3), GTPBP1 (GTP-binding protein 1 ) and/or SMC5 (Structural maintenance of chromosomes protein 5) in stimulated Tregs and/or unstimulated Teffs.

[108] "PPFIA1 " as used herein can mean any Protein Tyrosine Phosphatase Receptor Type F Polypeptide-lnteracting Protein Alpha-1 . For example, PPFIA1 may comprise or have the sequence of SEQ ID NO. 42 or be a sequence, which is 70 %, 80 %, 85 %, 90%, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 42. PPFIA1 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 42, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 42.

[109] "CHMP4B" as used herein can mean any Charged Multivesicular Body Protein 4B. For example, CHMP4B may comprise or have the sequence of SEQ ID NO. 43 or be a sequence, which is 70 %, 80 %, 85 %, 90%, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 43. CHMP4B can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 43, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 43.

[110] "CLIC1 " as used herein can mean any Chloride Intracellular Channel 1 . For example, CLIC1 may comprise or have the sequence of SEQ ID NO. 44 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 44. CLIC1 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 44, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 44.

[111] "RARA" as used herein can mean any Retinoic Acid Receptor, Alpha. For example, RARA may comprise or have the sequence of SEQ ID NO. 45 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 45. RARA can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 45, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 45.

[112] "MATR3" as used herein can mean any Matrin 3. For example, MATR3 may comprise or have the sequence of SEQ ID NO. 46 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 46. MATR3 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 46, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 46.

[113] "GTPBP1 " as used herein can mean any GTP-binding protein 1 . For example, GTPBP1 may comprise or have the sequence of SEQ ID NO. 47 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 47. GTPBP1 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 47, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 47.

[114] "SMC5" as used herein can mean any Structural maintenance of chromosomes protein 5. For example, SMC5 may comprise or have the sequence of SEQ ID NO. 48 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 48. SMC5 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 48, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 48.

[115] Additionally or alternatively, the inhibitor for use in the invention can decrease the interaction of DJ-1 with YWHAE (14-3-3 protein epsilon), MARS (Methionyl-TRNA Synthetase), TAGLN2 (transgelin 2), STMN1 (Stathmin 1 ), SART, VAV1 (Proto- oncogene vav), BCL1 1 B (B-cell lymphoma/leukemia 1 1 B), GIMAP5 (GTPase, IMAP family member 5), PTPRC (Protein tyrosine phosphatase, receptor type, C) and/or UBE1 (E1 ubiquitin-activating enzyme) in unstimulated Tregs and/or stimulated Teffs.

[116] "YWHAE" as used herein can mean any 14-3-3 protein epsilon. For example, YWHAE may comprise or have the sequence of SEQ ID NO. 49 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 49. YWHAE can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 49, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 49.

[117] "MARS" as used herein can mean any Methionyl-TRNA Synthetase. For example, MARS may comprise or have the sequence of SEQ ID NO. 50 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 50. MARS can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 50, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 50.

[118] "TAGLN2" as used herein can mean any transgelin 2. For example, TAGLN2 may comprise or have the sequence of SEQ ID NO. 51 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 51 . TAGLN2 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 51 , and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 51 .

[119] "STMN1 " as used herein can mean any Stathmin 1 . For example, STMN1 may comprise or have the sequence of SEQ ID NO. 52 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 52. STMN1 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 52, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 52.

[120] "SART" as used herein can mean any SART. For example, SART may comprise or have the sequence of SEQ ID NO. 53 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 53. SART can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 53, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 53.

[121] "VAV1 " as used herein can mean any Proto-oncogene vav. For example, VAV1 may comprise or have the sequence of SEQ ID NO. 54 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 54. VAV1 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 54, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 54.

[122] "BCL1 1 B" as used herein can mean any B-cell lymphoma/leukemia 1 1 B. For example, BCL1 1 B may comprise or have the sequence of SEQ ID NO. 55 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 55. BCL1 1 B can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 55, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 55.

[123] "GIMAP5" as used herein can mean any GTPase, IMAP family member 5. For example, GIMAP5 may comprise or have the sequence of SEQ ID NO. 56 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 56. GIMAP5 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 56, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 56.

[124] "PTPRC" as used herein can mean any Protein tyrosine phosphatase, receptor type, C. For example, PTPRC may comprise or have the sequence of SEQ ID NO. 57 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 57. PTPRC can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 57, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 57.

[125] Additionally or alternatively, the inhibitor for use in the invention can decrease the interaction of DJ-1 with EXOSC1 (Exosome Component 1 ) and/or EXOSC9 (Exosome component 9) in stimulated Tregs and/or stimulated Teffs.

[126] "EXOSC1 " as used herein can mean any Exosome Component 1 . For example, EXOSC1 may comprise or have the sequence of SEQ ID NO. 58 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 58. EXOSC1 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 58, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 58.

[127] "EXOSC9" as used herein can mean any Exosome component 9. For example, EXOSC9 may comprise or have the sequence of SEQ ID NO. 59 or be a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 59. EXOSC9 can also relate to nucleic acid molecules encoding a protein having or comprising SEQ ID NO. 59, and/or relate to a nucleic acid molecule ecoding a protein having or comprising a sequence, which is 70 %, 80 %, 85 %, 90 %, 95 %, 97 %, 99 % or 100 % identical to SEQ ID NO. 59.

[128] The term "interaction" as described herein can for example mean binding. The term "specifically binds" or "binds" as used herein is not intended to indicate that a binding protein or DJ-1 or any other "interaction partner" for any of the interactions as described herein binds exclusively to its intended target since a binding molecule binds to any polypeptide displaying the epitope(s) to which the binding molecule/protein binds. Rather, a binding molecule "specifically binds" if its affinity for its intended target is about 5-fold greater when compared to its affinity for a non- target molecule which does not display the appropriate epitope(s). Preferably the affinity of the binding molecule/protein will be at least about 5 fold, preferably 10 fold, more preferably 25-fold, even more preferably 50-fold, and most preferably 100-fold or more, greater for a target molecule than its affinity for a non-target molecule. For example, the binding protein/molecule can bind with affinities of at least about 10⁷ M^"1, and preferably between about 10⁸ M^"1 to about 10⁹ M^"1, about 10⁹ M^"1 to about 10¹⁰ M^"1, or about 10¹⁰ M^"1 to about 10¹² M^"1.

[129] Affinity can e.g. be calculated as K_d=koff/k₀n (k₀ff is the dissociation rate constant, K_on is the association rate constant and K_d is the equilibrium constant). Affinity can be determined at equilibrium by measuring the fraction bound (r) of labeled ligand at various concentrations (c). The data are graphed using the Scatchard equation: r/c=K(n-r): where r=moles of bound ligand/mole of receptor at equilibrium; c=free ligand concentration at equilibrium; K=equilibrium association constant; and n=number of ligand binding sites per receptor molecule. By graphical analysis, r/c is plotted on the Y-axis versus r on the X-axis, thus producing a Scatchard plot. Antibody affinity measurement by Scatchard analysis is well known in the art. See, e.g., van Erp et al., J. Immunoassay 12: 425-43, 1991 ; Nelson and Griswold, Comput. Methods Programs Biomed. 27: 65-8, 1988.

[1 30] The term "epitope" refers to an antigenic determinant capable of specific binding to a binding molecule/protein. Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three dimensional structural characteristics, as well as specific charge characteristics. Conformational and nonconformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents.

[1 31 ] The present invention contemplates that the cancer can be selected from the group consisting of adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain and spinal cord tumors, breast cancer, Castleman disease, cervical cancer, colon cancer, endometrial cancer, esophagus cancer, Ewing family of tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, Hodgkin disease, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), liver cancer, lymphoma, lymphoma of the skin, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumors, prostate cancer, rectum cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, basal and squamous cell cancer, melanoma, merkel cell cancer, small intestine cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, or Wilms tumor.

[132] The present invention envisions that the infectious disease can be of viral and/or bacterial origin. Exemplary infectious diseases include but are not limited to multidrug-resistant Acinetobacter baumannii (MDR-Ab), AIDS, Amebiasis, Anaplasmosis, Animal Bites, Animals in Public Settings, Anthrax, Antibiotic Use, Arboviral Encephalitis, Aseptic Meningitis, Avian Influenza, Babesiosis , Baylisascaris (Raccoon Roundworm), Bioterrorism, Bird Flu, Botulism, Brucellosis, Campylobacteriosis, Carbapenem Resistant Enterobacteriaceae (CRE), Catheter Associated Urinary Tract Infection (CAUTI), Central Line-Associated Blood Stream Infection (CLABSI), Chancroid, Chickenpox (Varicella), Chickenpox (Varicella), Chikungunya, Chlamydia Trachomatis, Chronic Wasting Disease, Cholera, Clostridium Difficile Infection, Cryptosporidiosis, Cyclospora Infection, Dengue Fever, Diphtheria, Eastern Equine Encephalitis, Ebola, Ehrlichiosis, E. Coli (STEC), Encephalitis, Arboviral, Enterovirus, Foodborne and Waterborne Diseases, Giardiasis, Gonococcal Disease, Haemophilus Influenzae, Hantavirus Disease, Healthcare Associated Infections, Healthcare Associated Infection Events, Hemolytic Uremic Syndrome, Hepatitis, Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis Delta, Hepatitis E, Herpes, Genital, Herpes Gladiatorum, HIV, Influenza (Seasonal & H1 N1 ), La Crosse Encephalitis, Legionellosis, Leptospirosis, Listeriosis, Lyme Disease, Malaria, Measles, Meningitis, Meningitis, Viral or Aseptic, Meningococcal Disease- Invasive, Methicillin Resistant Staphylococcus Aureus (MRSA), Middle East Respiratory Syndrome (MERS), Monkeypox, Mosquito-borne Illness, Multi-drug Resistant Organism (MDRO) Resources for Healthcare Facilities, Mumps, Norovirus, ORV (Oral Rabies Vaccination, Pandemic Influenza, Pertussis (Whooping Cough), Plague, Powassan Virus Disease, Pneumococcal Disease, Poliomyelitis, Psittacosis, Q Fever, Rabies, Rash Illness, Rheumatic Fever, Rocky Mountain Spotted Fever, Rubella Congenital Syndrome, Rubella (German Measles), Rubeola (Measles), Ricin, Salmonellosis (Except Typhoid), Scabies, Severe Acute Respiratory Syndrome (SARS), Shiga Toxin-Producing E.coli (STEC), Shigellosis, Smallpox, St. Louis Encephalitis, Staphylococcus Aureus Infections, Streptococcal Disease, Group A Invasive or Streptococcal TSS, Streptococcal TSS or Streptococcal Disease, Group A, Streptococcal Disease, Invasive Group B, Streptococcal Pneumoniae, Surgical Site Infection, Swine Origin Influenza, Syphilis, Tetanus, Toxic Shock Syndrome, Trichinosis, Tuberculosis, Tularemia, Typhoid Fever, Vancomycin-Resistant Entercoccus, Vancomycin Resistant Staphylococcus aureus or Vancomycin Resistant Intermediate Resistance, Varicella (Chicken Pox), Vibriosis, Viral Hemorrhagic Fever, West Nile Virus, Western Equine Encephalitis, Yellow Fever or Yersinia Enterocolitica.

[133] The present invention envisions that inhibtors can be used to treat or prevent autoimmune diseases. An "autoimmune disease" occurs when a specific adaptive immune response is mounted against self-antigens. The normal consequence of an adaptive immune response against a foreign antigen is the clearance of the antigen from the body. Exemplary autoimmune diseases include but are not limited to Systemic lupus erythematosus (SLE), Goodpasture's syndrome, Sarcoidosis, Scleroderma, Rheumatoid arthritis, Dermatomyositis, Sjogren's Syndrome, Scleroderma, Dermatomyositis, Psoriasis, Vitiligo, Alopecia areata, Type 1 diabetes mellitus, Autoimmune pancreatitis, Hashimoto's thyroiditis, Addison's disease, Multiple sclerosis, Myasthenia gravis, Polyarteritis nodosa, Idiopathic thrombocytopenic purpura, Hemolytic anemia, Antiphospholipid antibody syndrome, Pernicious anemia, Gastrointestinal diseases, Celiac disease, Inflammatory bowel disease, Autoimmune hepatitis or Primary biliary cirrhosis.

[134] Inhibitors used in the present invention can also be used in co-treatment with other therapies such as other anti-autoimmune disease, anti-allergy, anti-infectious and/or other disease anti-cancer therapies. This co-treatment can include administration of an inhibitor used in the present invention, preferably in the form of a medicament, to a subject suffering from a condition comprising autoimmune disease, allergy, infectious and/or cancer therapies. Similarly included is the administration of an inhibitor used in the present invention, preferably in the form of a drug/medicament, to a subject.

[135] The inhibitor(s) used in the present invention can be administered by any suitable route. Exemplary routes of administration include oral, intravenous, intrapleural, intramuscular, topical or via inhalation.

[136] The present invention also relates to a pharmaceutical composition comprising the inhibitor as described herein. The pharmaceutical composition can be administered to a subject. Such pharmaceutical compositions can be administered in any suitable unit dosage form. Suitable oral formulations can be in the form of tablets, capsules, suspension, syrup, chewing gum, wafer, elixir, and the like. Pharmaceutically acceptable carriers such as binders, excipients, lubricants, and sweetening or flavoring agents can be included in the pharmaceutical compositions. If desired, conventional agents for modifying tastes, colors, and shapes of the special forms can also be included.

[137] For injectable formulations, the pharmaceutical compositions can be in lyophilized powder in admixture with suitable excipients in a suitable vial or tube. Before use in the clinic, the inhibitors may be reconstituted by dissolving the lyophilized powder in a suitable solvent system to form a composition suitable for intravenous or intramuscular injection.

[138] In addition, the present invention relates to a use of an inhibitor of DJ-1 (PARK7) for use in the treatment or prevention of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer.

[139] The present invention also relates to a method for screening for an inhibitor or activator of DJ-1 , the method comprising

(a) contacting Tregs with a nucleic acid molecule, preferably a siRNA or a miRNA, a binding protein, a small molecule or a compound of interest;

(b) measuring suppressor function of Tregs, wherein a increase in suppressor function of said Tregs compared to said Tregs before contacting indicates that the nucleic acid molecule, preferably a siRNA or miRNA, the binding protein, the small molecule or the compound of interest serves as an inhibitor of DJ-1 , or wherein an decrease in the suppressor function of said Tregs compared to said Tregs before contacting indicates that the nucleic acid molecule, preferably a siRNA or a miRNA, binding protein of interest serves as an activator of DJ-1 .

[140] The present invention also relates to a method for determining whether or not a cell is susceptible to the treatment with an inhibitor as described herein, comprising determining whether or not said cell expresses DJ-1 .

[141] Also, the present invention relates to a kit comprising an inhibitor of DJ-1 as described herein. The kit can further comprise one or more of

(i) polyethylenimine (PEI), preferably low molecular weight PEI,

(ii) a plasmid vector

(iii) a synthetic or natural nanoparticle as described herein.

[142] The present invention also relates to an inhibitor of DJ-1 (PARK7) as described herein for use in treating or preventing of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer, wherein the treating or preventing comprises

(i) contacting Tregs and/or Teffs with the inhibitor.

[143] In addition, the present invention relates to an inhibitor of DJ-1 (PARK7) as described herein for use in treating or preventing of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer, wherein the treating or preventing comprises

(i) obtaining Tregs and/or Teffs from a subject;

(ii) contacting said Tregs and/or Teffs with the inhibitor, and

(iii) re-introducing said Tregs and/or Teffs to the subject.

[144] The present invention also relates to a method of treating of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer, the method comprising

(i) administering a therapeutically effective amount of an inhibitor of DJ-1 (PARK7) as described herein to the subject.

[145] The methods and used described herein as well as the inhibitor for use as described herein can be utilized to treat a subject. The "subject" when used herein can be a vertebrate such as a mammal. Mammals include, but are not limited to, farm animals, sport animals, pets, primates, mice and rats. Preferably, a mammal is a human, dog, cat, cow, pig, mouse, rat etc., particularly preferred, it is a human. Human beings are preferred. The "subject", which may be treated with one or more inhibitors or pharmaceutical compositions as described herein, can be a vertebrate, preferably a vertebrate that has an adaptive immune system. In the context of the present invention the term "subject" can mean an individual in need of a treatment and/or prophylaxis of autoimmune disease, allergy, infectious disease or cancer. The subject can also be a patient suffering from autoimmune disease, allergy, infectious disease or cancer or being at a risk thereof.

[146] The present invention also reltes to a use of an inhibitor as described herein, for the preparation of a medicament for the treatment of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer.

[147] The present invention is further characterized by the following items:

[148] 1 . Inhibitor of DJ-1 (PARK7) for use in the treatment or prevention of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer.

[149] 2. Inhibitor for the use of item 1 , wherein the inhibitor is a nucleic acid molecule, preferably a siRNA or miRNA, a binding protein, a small molecule or a compound.

[150] 3. Inhibitor for the use of item 2, wherein the binding protein is selected from the group consisting of an antibody, preferably a divalent antibody fragment or a monovalent antibody fragment, or a proteinaceous binding molecule with antibodylike binding properties.

[151] 4. Inhibitor for the use of item 3, wherein the divalent antibody fragment is an (Fab)2'-fragment, a divalent single-chain Fv fragment, a bsFc-1/2-dimer or a bsFc- CH3-1/2 dimer.

[152] 5. Inhibitor for the use of item 3, wherein the monovalent antibody fragment is selected from the group consisting of a Fab fragment, a Fv fragment, a single-chain Fv fragment (scFv) or an scFv-Fc fragment.

[153] 6. Inhibitor for the use of item 3, wherein the proteinaceous binding molecule with antibody-like binding properties is selected from the group of an aptamer, a mutein based on a polypeptide of the lipocalin family, a glubody, a protein based on the ankyrin scaffold, a protein based on the crystalline scaffold, an adnectin, an avimer or a (recombinant) receptor protein.

[154] 7. Inhibitor for use of item 2, wherein the nucleic acid molecule, preferably a siRNA, has a sequence identity of at least 50 %, 60%, 70%, 80%, 90%, 95%, 98% 99% or 100% to SEQ ID NO: 1 . [155] 8. Inhibitor for use of item 2 or 7, wherein the nucleic acid molecule, preferably a siRNA or miRNA, are provided within a plasmid vector and/or are modified or encapsulated by synthetic or natural nanoparticles.

[156] 9. Inhibitor for use of item 8, wherein the synthetic or natural lipid nanoparticles comprise lipids as well as polymers and/or metals.

[157] 10. Inhibitor for use of item 8 or 9, wherein the nanoparticle comprises one or more of natural or synthetic lipids (e.g., liposomes, micelles), polymers (e.g, chitosan, poly(lactic-co-glycolic) acid (PLGA), polylactic acid (PLA), polyethilenimine (PEI), atelocollagen), carbon nanotubes, quantum dots, gold nanoshells or iron oxide magnetic.

[158] 1 1 . Inhibitor for use of any one of items 8-10, wherein the nanoparticle is biodegradable.

[159] 12. Inhibitor for use of item 10 or 1 1 , wherein the nanoparticle is a liposomal nanoparticle.

[160] 13. Inhibitor for use of item 12, wherein the liposomal nanoparticle is a cationic-lipid based liposome, neutral lipid-based nanoliposome, a solid lipid-based systems (SNALP and SLN) or lipidoid nanoparticle.

[161] 14. The inhibitor for the use of any one of items 1 -13, wherein the inhibitor decreases expression of DJ-1 in unstimulated or stimulated T effector cells (Teffs) and/or unstimulated or stimulated regulatory T cells (Tregs), preferably the Teff is a human Teff and the Treg is a human Treg.

[162] 15. Inhibitor of any one of items 1 -14, wherein the Treg is a human natural Treg (nTreg) and/or a Treg with impaired suppressor function.

[163] 16. Inhibitor for the use of any one of items 1 -15, wherein the inhibitor increases Treg suppressor function.

[164] 17. Inhibitor for the use of any one of items 1 -15, wherein the inhibitor increases Treg suppressor function in a Treg compared to the Treg before it has been contacted with the inhibitor.

[165] 18. Inhibitor for the use of item 16 or 17, wherein the inhibitor increases Treg suppressor function at high ratios such as ratios of 1 :4 or 1 :8 (Treg eff ratios).

[166] 19. Inhibitor for the use of any one of items 16-18, wherein the inhibitor does not increase Treg suppressor function at low ratios (Treg:Teff ratios).

[167] 20. Inhibitor for use of any of items 1 -19, wherein the inhibitor increases Treg suppressive function of Tregs with an impaired suppressor function.

[168] 21 . Inhibitor for use of item 20, wherein the Treg with an impaired suppressor function is a Treg that has been obtained from a subject having an autoimmune disease, allergy, infectious disease or cancer.

[169] 22. Inhibitor for use of item 20 or 21 , wherein the Treg with an impaired suppressor function is a Treg having a FOXP3 deficiency.

[170] 23. Inhibitor for use of any one of items 19-22, wherein the inhibitor up- regulates one or more genes in the Treg with an impaired suppressor function.

[171] 24. Inhibitor for use of item 23, wherein the one or more genes are selected from the group consisting of FOXP3 (forkhead box P3), GARP (Leucine-Rich Repeat- Containing Protein 32), CTLA4 (cytotoxic T-lymphocyte-associated protein 4) or EOS (IKZF4; IKAROS Family Zinc Finger 4).

[172] 25. Inhibitor for use of any one of items 1 -24, wherein the inhibitor increases the reactive oxygen species (ROS) burst level in Tregs, preferably nTregs.

[173] 25. Inhibitor for use of item 24, wherein the ROS is selected from the group consisting of peroxides, superoxides, hydroxyl radicals, or singlet oxygen.

[174] 26. Inhibitor for the use of any one of items 1 -25, wherein the inhibitor decreases the expression of UBE1 (E1 ubiquitin-activating enzyme), E2 ubiquitin- conjugating enzymes such as UBE22D3 and UBE2O and/or SKP2 (S-phase kinase- associated protein 2).

[175] 27. Inhibitor for the use of any one of items 1 -26, wherein the inhibitor increases the expression of E3 ubiquitin-ligases such as UBE4B (Ubiquitin conjugation factor E4 B), TRIP12 (Thyroid Hormone Receptor Interactor 12) and/or SMURF2 (SMAD Specific E3 Ubiquitin Protein Ligase 2).

[176] 28. Inhibitor for the use of any one of items 1 -27, wherein the inhibitor decreases the interaction of DJ-1 with GZMB (Granzyme B).

[177] 29. Inhibitor for the use of any one of items 1 -28, wherein the inhibitor decreases the interaction of DJ-1 with UPF1 (Regulator of nonsense transcripts 1 ), PPP1 CB (Serine/threonine-protein phosphatase PP1 -beta catalytic subunit), ATP5D (ATP synthase subunit delta, mitochondrial), EIF2A (Eukaryotic translation initiation factor 2A), EIF5B (Eukaryotic translation initiation factor 5B), MAP4K1 (Mitogen- activated protein kinase 1 ) and/or ANXA4 (Annexin IV) in stimulated Tregs.

[178] 30. Inhibitor for the use of any one of items 1 -29, wherein the inhibitor decreases the interaction of DJ-1 with LGALS3BP (Galectin-3-binding protein), MOV10 (RISC complex RNA helicase), PDHB (pyruvate dehydrogenase (lipoamide) beta) in unstimulated Tregs.

[179] 31 . Inhibitor for the use of any one of items 1 -30, wherein the inhibitor decreases the interaction of DJ-1 with PPFIA1 (Protein Tyrosine Phosphatase Receptor Type F Polypeptide-lnteracting Protein Alpha-1 ), CHMP4B (Charged Multivesicular Body Protein 4B), CLIC1 (Chloride Intracellular Channel 1 ), RARA (Retinoic Acid Receptor, Alpha), MATR3 (Matrin 3), GTPBP1 (GTP-binding protein 1 ) and/or SMC5 (Structural maintenance of chromosomes protein 5) in stimulated Tregs and/or unstimulated Teffs.

[180] 32. Inhibitor for the use of any one of items 1 -31 , wherein the inhibitor decreases the interaction of DJ-1 with YWHAE (14-3-3 protein epsilon), MARS (Methionyl-TRNA Synthetase), TAGLN2 (transgelin 2), STMN1 (Stathmin 1 ), SART, VAV1 (Proto-oncogene vav), BCL1 1 B (B-cell lymphoma/leukemia 1 1 B), GIMAP5 (GTPase, IMAP family member 5), PTPRC (Protein tyrosine phosphatase, receptor type, C) and/or UBE1 (E1 ubiquitin-activating enzyme) in unstimulated Tregs and/or stimulated Teffs.

[181] 33. Inhibitor for the use of any one of items 1 -31 , wherein the inhibitor decreases the interaction of DJ-1 with EXOSC1 (Exosome Component 1 ) and/or EXOSC9 (Exosome component 9) in stimulated Tregs and/or stimulated Teffs.

[182] 34. Inhibitor for use of any one of items 28-32, wherein the interaction is binding.

[183] 35. Inhibitor for the use of any one of items 1 -34, wherein the cancer is selected from the group consisting of adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain and spinal cord tumors, breast cancer, Castleman disease, cervical cancer, colon cancer, endometrial cancer, esophagus cancer, Ewing family of tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, Hodgkin disease, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), liver cancer, lymphoma, lymphoma of the skin, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumors, prostate cancer, rectum cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer, basal and squamous cell cancer, melanoma, merkel cell cancer, small intestine cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, or Wilms tumor.

[184] 36. Pharmaceutical composition comprising the inhibitor as defined in any one of items 1 -34.

[185] 37. Use of an inhibitor of DJ-1 (PARK7) for use in the treatment or prevention of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer.

[186] 38. Method for screening for an inhibitor or activator of DJ-1 , the method comprising

(a) contacting Tregs with a the nucleic acid molecule, preferably a siRNA or a miRNA, a binding protein, a small molecule or a compound of interest;

(b) measuring suppressor function of Tregs, wherein a increase in suppressor function of said Tregs compared to said Tregs before contacting indicates that the the nucleic acid molecule, preferably a siRNA or miRNA, the binding protein, the small molecule or the compound of interest serves as an inhibitor of DJ-1 , or wherein an decrease in the suppressor function of said Tregs compared to said Tregs before contacting indicates that the the nucleic acid molecule, preferably a siRNA ormiRNA, the binding protein, the small molecule or the compound of interest serves as an activator of DJ-1 .

[187] 39. Method for determining whether or not a cell is susceptible to the treatment with an inhibitor as defined in any one of items 1 -34, comprising determining whether or not said cell expresses DJ-1 .

[188] 40. Kit comprising an inhibitor of DJ-1 as defined in any one of items 1 -34. [189] 41 . Kit of item 40, further comprising one or more of

(i) polyethylenimine (PEI), preferably low molecular weight PEI,

(ii) a plasmid vector

(iii) a synthetic or natural nanoparticle as defined in any one of items 8-13.

[190] 42. Inhibitor of DJ-1 (PARK7) for use in treating or preventing of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer, wherein the treating or preventing comprises

(i) contacting Tregs and/or Teffs with the inhibitor.

[191] 43. Inhibitor of DJ-1 (PARK7) for use in treating or preventing of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer, wherein the treating or preventing comprises

(i) obtaining Tregs and/or Teffs from a subject;

(ii) contacting said Tregs and/or Teffs with the inhibitor, and

(iii) re-introducing said Tregs and/or Teffs to the subject.

[192] 44. Method of treating of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer, the method comprising

[193] 45. Use of an inhibitor of any one of items 1 -34, for the preparation of a medicament for the treatment of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer.

[194] The following sequences have been used in the present invention:

SEQ ID Type of seq Sequence

NO:

1 Anti-DJ-1 si NA AATGGAGGTCATTACACCTAC

2 Anti-FOXP3 CAG CTG GAG GGC TGC ACC CAA siRNA

3 Primer Human TTG TAG GCT GAG AAA TCT CTG TG

PARK7/DJ-1

forward (5-3)

4 Primer PARK7 ATC CAT TCT CAC TGT GTT CGC

reverse (5-3)

5 Primer FOXP3 ACC TAC GCC ACG CTC ATC

forward

6 Primer FOXP3 TCATTG AGTGTC CGC TGC T

reverse

7 Primer CTLA4 TGC AGC AGT TAG TTC GGG GTT GTT

forward

8 Primer CTLA4 CTG GCT CTG TTG GGG GCATTT TC

reverse

9 Primer TGFB1 CGC AAG GAC CTC GGC TGG AAG TGG

forward

10 Primer TGFB1 GAG GCG CCC GGG TTA TGC TGG TTG

reverse

11 Primer GARP GAT GGG GAA ACT GAG GCT TAG GAA

forward

12 Primer GARP ACC CCC AAT CTC ACC CCA CAA ATA

reverse

13 Primer LGMN CTC GCT CCA GGA CCT TCT TCA CAA

forward

14 Primer LGMN GCT TCC TGC TCC TCA AAA CTA ACA

reverse

15 Primer IL4 CGG CAA CTT TGT CCA CGG A

forward

16 Primer IL4 TCT GTT ACG GTC AAC TCG GTG

reverse

>sp 1 Q99497 1 PA MASKRALVI LAKGAEEMETVIPVDVMRRAGIKVTVAGLAGKDPVQCSRDVVICP

SEQ I D

RK7_H UMAN DASLEDAKKEGPYDVVVLPGGN LGAQN LSESAAVKEILKEQENRKGLIAAICAGPT

NO. Protein ALLAHEIGFGSKVTTH PLAKDKMM NGGHYTYSEN RVEKDGLI LTSRGPGTSFEFAL

17 deglycase DJ-1 AIVEALNGKEVAAQVKAPLVLKD

OS=Homo

sapiens

GN=PARK7 PE=1

SV=2

>gi 1 1832276761 TGAGTCTGCGCAGTGTGGGGCTGAGGGAGGCCGGACGGCGCGCGTGCGTGC

SEQ I D

ref | NM_007262 TGGCGTGCGTTCA 1 1 1 1 CAGCCTGGTGTGGGGTGAGTGGTACCCAACGGGCC

NO.

•4 | GGGGCGCCGCGTCCGCAGGAAGAGGCGCGGGGTGCAGGCTTGTAAACATAT

18 Homo sapiens A AC ATA AAA ATG G CTTCC A AA AG AG CTCTG GTC ATCCTG G CTA AAG GAG C AG

Parkinsonism AGGAAATGGAGACGGTCATCCCTGTAGATGTCATGAGGCGAGCTGGGATTAA associated GGTCACCGTTGCAGGCCTGGCTGGAAAAGACCCAGTACAGTGTAGCCGTGAT deglycase GTGGTCATTTGTCCTGATGCCAGCCTTGAAGATGCAAAAAAAGAGGGACCAT (PARK7), ATGATGTGGTGGTTCTACCAGGAGGTAATCTGGGCGCACAGAATTTATCTGA transcript GTCTGCTGCTGTGAAGGAGATACTGAAGGAGCAGGAAAACCGGAAGGGCCT variant 1, mRNA GATAGCCGCCATCTGTGCAGGTCCTACTGCTCTGTTGGCTCATGAAATAGGTT

TTGGAAGTAAAGTTACAACACACCCTCTTGCTAAAGACAAAATGATGAATGGA

GGTCATTACACCTACTCTGAGAATCGTGTGGAAAAAGACGGCCTGATTCTTAC

AAGCCGGGGGCCTGGGACCAGCTTCGAGTTTGCGCTTGCAATTGTTGAAGCC

CTG AATG GCAAGGAGGTGGCGG CTC AAGTG A AG G CTCC ACTTGTTCTTA AAG

ACTAGAGCAGCGAACTGCGACGATCACTTAGAGAAACAGGCCGTTAGGAATC

C ATTCTC ACTGTGTTCG CTCTAA AC A AA AC AGTG GT AG GTT AATGTGTTC AG A

AGTCGCTGTCCTTACTAC 1 1 1 1 GCGGAAGTATGGAAGTCACAACTACACAGAG

ATTTCTCAGCCTACAAATTGTGTCTATACATTTCTAAGCCTTGTTTGCAGAATAA

AC AGG G C ATTTAG C A AACT AA AA AA AA AA A AA AA AA AA

>gi 1 183227677 1 TGAGTCTGCGCAGTGTGGGGCTGAGGGAGGCCGGACGGCGCGCGTGCGTGC

SEQ I D

ref | NM_001123 TGGCGTGCGTTCA 1 1 1 1 C AG CCTG GTGTG G GG CTTGT AA AC AT AT AAC ATA AA

NO. 377.1 1 Homo AATGGCTTCCAAAAGAGCTCTGGTCATCCTGGCTAAAGGAGCAGAGGAAATG

19 sapiens GAGACGGTCATCCCTGTAGATGTCATGAGGCGAGCTGGGATTAAGGTCACCG

Parkinsonism TTGCAGGCCTGGCTGGAAAAGACCCAGTACAGTGTAGCCGTGATGTGGTCAT associated TTGTCCTGATGCCAGCCTTGAAGATGCAAAAAAAGAGGGACCATATGATGTG deglycase GTG GTTCTACC AG G AG GTA ATCTG G G CG C AC AG A ATTTATCTG AGTCTG CTG C

(PARK7), TGTGAAGGAGATACTGAAGGAGCAGGAAAACCGGAAGGGCCTGATAGCCGC transcript C ATCTGTG C AG GTCCTACTG CTCTGTTG G CTC ATG AA AT AG G 1 1 1 1 GGAAGTA variant 2, mRNA AAGTTACAACACACCCTCTTGCTAAAGACAAAATGATGAATGGAGGTCATTAC

ACCTACTCTGAGAATCGTGTGGAAAAAGACGGCCTGATTCTTACAAGCCGGG

GGCCTGGGACCAGCTTCGAGTTTGCGCTTGCAATTGTTGAAGCCCTGAATGGC

AAGGAGGTGGCGGCTCAAGTGAAGGCTCCACTTGTTCTTAAAGACTAGAGCA

GCGAACTGCGACGATCACTTAGAGAAACAGGCCGTTAGGAATCCATTCTCACT

GTGTTCG CTCTAA AC AA AAC AGTG GTAG GTTA ATGTGTTC AG A AGTCG CTGTC

CTTACTAC 1 1 1 1 GCGGAAGTATGGAAGTCACAACTACACAGAGATTTCTCAGC

CT AC AA ATTGTGTCTATAC ATTTCT AAG CCTTGTTTG C AG A ATA A AC AG G G CAT

TT AG C AA ACTA AAAA AAA AAAAAA AAA AA

FOXP3 MPN PRPGKPSAPSLALGPSPGASPSWRAAPKASDLLGARGPGGTFQGRDLRGG

SEQ I D

(forkhead box AHASSSSLN PM PPSQLQLPTLPLVMVAPSGARLGPLPH LQALLQDRPH FMHQLS

NO. P3) TVDAHARTPVLQVH PLESPAMISLTPPTTATGVFSLKARPGLPPGINVASLEWVSR

20 >sp | Q9BZSl | FO EPALLCTFPN PSAPRKDSTLSAVPQSSYPLLANGVCKWPGCEKVFEEPEDFLKHCQ XP3_H UMAN ADHLLDEKGRAQCLLQREMVQSLEQQLVLEKEKLSAMQAHLAGKMALTKASSV Forkhead box ASSDKGSCCIVAAGSQGPVVPAWSGPREAPDSLFAVRRHLWGSHGNSTFPEFLH protein P3 N MDYFKFH NM RPPFTYATLIRWAILEAPEKQRTLN EIYHWFTRMFAFFRNH PAT

WKNAIRH N LSLH KCFVRVESEKGAVWTVDELEFRKKRSQRPSRCSNPTPGP

GARP (Leucine- MRPQILLLLALLTLGLAAQHQDKVPCKMVDKKVSCQVLGLLQVPSVLPPDTETLD

SEQ I D

Rich Repeat- LSGNQLRSI LASPLGFYTALRHLDLSTN EISFLQPGAFQALTHLEHLSLAH N RLAMA

NO. Containing TALSAGGLGPLPRVTSLDLSGNSLYSGLLERLLGEAPSLHTLSLAENSLTRLTRHTFR

21 Protein 32) DMPALEQLDLHSNVLMDI EDGAFEGLPRLTH LN LSRNSLTCISDFSLQQLRVLDLS >sp | Q14392 | LR CNSI EAFQTASQPQAEFQLTWLDLREN KLLHFPDLAALPRLIYLNLSNN LI RLPTGP C32_H UMAN PQDSKGIHAPSEGWSALPLSAPSGNASGRPLSQLLN LDLSYNEIELIPDSFLEHLTSL Leucine-rich CFLN LSRNCLRTFEARRLGSLPCLM LLDLSH NALETLELGARALGSLRTLLLQGNAL repeat- RDLPPYTFANLASLQRLN LQGNRVSPCGGPDEPGPSGCVAFSGITSLRSLSLVDN EI containing ELLRAGAFLHTPLTELDLSSN PGLEVATGALGGLEASLEVLALQGNGLMVLQVDLP protein 32 CFICLKRLN LAEN RLSHLPAWTQAVSLEVLDLRNNSFSLLPGSAMGGLETSLRRLYL

QGNPLSCCGNGWLAAQLHQGRVDVDATQDLICRFSSQEEVSLSHVRPEDCEKG

GLKN IN LI I ILTFILVSAI LLTTLAACCCVRRQKFNQQYKA CTLA4 (cytotoxic MACLGFQRHKAQLNLATRTWPCTLLFFLLFIPVFCKAMHVAQPAVVLASSRGIAS

SEQ ID

T-lymphocyte- FVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSG

NO. associated NQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEPCPDSDFLLW

22 protein 4) ILAAVSSGLFFYSFLLTAVSLSKMLKKRSPLTTGVYVKMPPTEPECEKQFQPYFIPIN >sp|P16410|CT

LA4_HUMAN

Cytotoxic T- lymphocyte

protein 4

EOS (IKZF4; MHTPPALPRRFQGGGRVRTPGSHRQGKDNLERDPSGGCVPDFLPQAQDSNHFI

SEQ ID IKAROS Family MESLFCESSGDSSLEKEFLGAPVGPSVSTPNSQHSSPSRSLSANSIKVEMYSDEESS NO. Zinc Finger 4) RLLGPDERLLEKDDSVIVEDSLSEPLGYCDGSGPEPHSPGGIRLPNGKLKCDVCGM

23 >sp|Q9H2S9|IK VCIGPNVLMVHKRSHTGERPFHCNQCGASFTQKGNLLRHIKLHSGEKPFKCPFCN ZF4_HUMAN YACRRRDALTGHLRTHSVSSPTVGKPYKCNYCGRSYKQQSTLEEH KERCH NYLQS Zinc finger LSTEAQALAGQPGDEIRDLEMVPDSMLHSSSERPTFIDRLANSLTKRKRSTPQKFV protein Eos GEKQMRFSLSDLPYDVNSGGYEKDVELVAHHSLEPGFGSSLAFVGAEHLRPLRLP

PTNCISELTPVISSVYTQMQPLPGRLELPGSREAGEGPEDLADGGPLLYRPRGPLT

DPGASPSNGCQDSTDTESNHEDRVAGVVSLPQGPPPQPPPTIVVGRHSPAYAKE

DPKPQEGLLRGTPGPSKEVLRVVGESGEPVKAFKCEHCRILFLDHVMFTIHMGCH

GFRDPFECNICGYHSQDRYEFSSHIVRGEHKVG

UBE1 (El MSSSPLSKKRRVSGPDPKPGSNCSPAQSVLSEVPSVPTNGMAKNGSEADIDEGLY

SEQ ID

ubiquitin- SRQLYVLGHEAMKRLQTSSVLVSGLRGLGVEIAKNIILGGVKAVTLHDQGTAQWA

NO. activating DLSSQFYLREEDIGKNRAEVSQPRLAELNSYVPVTAYTGPLVEDFLSGFQVVVLTN

24 enzyme) TPLEDQLRVGEFCHNRGIKLVVADTRGLFGQLFCDFGEEMILTDSNGEQPLSAMV >sp|P22314|UB SMVTKDNPGVVTCLDEARHGFESGDFVSFSEVQGMVELNGNQPMEIKVLGPYT A1_HUMAN FSICDTSNFSDYIRGGIVSQVKVPKKISFKSLVASLAEPDFVVTDFAKFSRPAQLHIG Ubiquitin-like FQALHQFCAQHGRPPRPRNEEDAAELVALAQAVNARALPAVQQNNLDEDLIRKL modifier- AYVAAGDLAPINAFIGGLAAQEVMKACSGKFMPIMQWLYFDALECLPEDKEVLT activating EDKCLQRQNRYDGQVAVFGSDLQEKLGKQKYFLVGAGAIGCELLKNFAMIGLGC enzyme 1 GEGGEIIVTDMDTIEKSNLNRQFLFRPWDVTKLKSDTAAAAVRQMNPHIRVTSH

QNRVGPDTERIYDDDFFQNLDGVANALDNVDARMYMDRRCVYYRKPLLESGTL

GTKGNVQVVIPFLTESYSSSQDPPEKSIPICTLKNFPNAIEHTLQWARDEFEGLFKQ

PAENVNQYLTDPKFVERTLRLAGTQPLEVLEAVQRSLVLQRPQTWADCVTWACH

HWHTQYSNNIRQLLHNFPPDQLTSSGAPFWSGPKRCPHPLTFDVNNPLHLDYV

MAAANLFAQTYGLTGSQDRAAVATFLQSVQVPEFTPKSGVKIHVSDQELQSANA

SVDDSRLEELKATLPSPDKLPGFKMYPIDFEKDDDSNFHMDFIVAASNLRAENYDI

PSADRHKSKLIAGKIIPAIATTTAAVVGLVCLELYKVVQGHRQLDSYKNGFLNLALP

FFGFSEPLAAPRHQYYNQEWTLWDRFEVQGLQPNGEEMTLKQFLDYFKTEHKLE

ITMLSQGVSMLYSFFMPAAKLKERLDQPMTEIVSRVSKRKLGRHVRALVLELCCN

DESGEDVEVPYVRYTIR

E2 ubiquitin- MALKRINKELSDLARDPPAQCSAGPVGDDMFHWQATIMGPNDSPYQGGVFFLT

SEQ ID

conjugating IHFPTDYPFKPPKVAFTTRIYHPNINSNGSICLDILRSQWSPALTISKVLLSICSLLCDP

NO. enzyme NPDDPLVPEIARIYKTDRDKYNRISREWTQKYAM

25 UBE22D3

>sp|P61077|UB

2D3_HUMAN

Ubiquitin- conjugating

enzyme E2 D3

E2 ubiquitin- MADPAAPTPAAPAPAQAPAPAPEAVPAPAAAPVPAPAPASDSASGPSSDSGPE

SEQ ID

conjugating AGSQRLLFSHDLVSGRYRGSVHFGLVRLIHGEDSDSEGEEEGRGSSGCSEAGGAG NO. enzyme HEEGRASPLRRGYVRVQWYPEGVKQHVKETKLKLEDRSVVPRDVVRHMRSTDS

26

UBE20 QCGTVIDVNIDCAVKLIGTNCIIYPVNSKDLQHIWPFMYGDYIAYDCWLGKVYDLK

>sp I Q9C0C91 U NQIILKLSNGARCSMNTEDGAKLYDVCPHVSDSGLFFDDSYGFYPGQVLIGPAKIF BE20 HUMAN SSVQWLSGVKPVLSTKSKFRVVVEEVQVVELKVTWITKSFCPGGTDSVSPPPSVIT (E3- QENLGRVKRLGCFDHAQRQLGERCLYVFPAKVEPAKIAWECPEKNCAQGEGSM independent) E2 AKKVKRLLKKQVVRIMSCSPDTQCSRDHSMEDPDKKGESKTKSEAESASPEETPD ubiquitin- GSASPVEMQDEGAEEPHEAGEQLPPFLLKEGRDDRLHSAEQDADDEAADDTDD conjugating TSSVTSSASSTTSSQSGSGTSRKKSIPLSIKNLKRKHKRKKNKITRDFKPGDRVAVEV enzyme VTTMTSADVMWQDGSVECNIRSNDLFPVHHLDNNEFCPGDFVVDKRVQSCPD

PAVYGVVQSGDHIGRTCMVKWFKLRPSGDDVELIGEEEDVSVYDIADHPDFRFR

TTDIVIRIGNTEDGAPHKEDEPSVGQVARVDVSSKVEVVWADNSKTIILPQHLYNI

ESEIEESDYDSVEGSTSGASSDEWEDDSDSWETDNGLVEDEHPKIEEPPIPPLEQP

VAPEDKGVVISEEAATAAVQGAVAMAAPMAGLMEKAGKDGPPKSFRELKEAIKI

LESLKNMTVEQLLTGSPTSPTVEPEKPTREKKFLDDIKKLQENLKKTLDNVAIVEEEK

MEAVPDVERKEDKPEGQSPVKAEWPSETPVLCQQCGGKPGVTFTSAKGEVFSVL

EFAPSNHSFKKIEFQPPEAKKFFSTVRKEMALLATSLPEGIMVKTFEDRMDLFSALI

KGPTRTPYEDGLYLFDIQLPNIYPAVPPHFCYLSQCSGRLNPNLYDNGKVCVSLLGT

WIGKGTERWTSKSSLLQVLISIQGLILVNEPYYNEAGFDSDRGLQEGYENSRCYNE

MALIRVVQSMTQLVRRPPEVFEQEIRQHFSTGGWRLVNRIESWLETHALLEKAQ

ALPNGVPKASSSPEPPAVAELSDSGQQEPEDGGPAPGEASQGSDSEGGAQGLAS

ASRDHTDQTSETAPDASVPPSVKPKKRRKSYRSFLPEKSGYPDIGFPLFPLSKGFIKS

IRGVLTQFRAALLEAGMPECTEDK

SKP2 (S-phase MHRKHLQEIPDLSSNVATSFTWGWDSSKTSELLSGMGVSALEKEEPDSENIPQEL

SEQID

kinase- LSNLGHPESPPRKRLKSKGSDKDFVIVRRPKLNRENFPGVSWDSLPDELLLGIFSCL

NO. associated CLPELLKVSGVCKRWYRLASDESLWQTLDLTGKNLHPDVTGRLLSQGVIAFRCPRS

27 protein 2) FMDQPLAEHFSPFRVQHMDLSNSVIEVSTLHGILSQCSKLQNLSLEGLRLSDPIVN >sp|Q13309|SK TLAKNSNLVRLNLSGCSGFSEFALQTLLSSCSRLDELNLSWCFDFTEKHVQVAVAH P2_HUMAN S- VSETITQLNLSGYRKNLQKSDLSTLVRRCPNLVHLDLSDSVMLKNDCFQEFFQLNY phase kinase- LQHLSLSRCYDIIPETLLELGEIPTLKTLQVFGIVPDGTLQLLKEALPHLQINCSHFTTI associated ARPTIGNKKNQEIWGIKCRLTLQKPSCL

protein 2

E3 ubiquitin- MEELSADEIRRRRLARLAGGQTSQPTTPLTSPQRENPPGPPIAASAPGPSQSLGLN

SEQID

ligases UBE4B VHNMTPATSPIGASGVAHRSQSSEGVSSLSSSPSNSLETQSQSLSRSQSMDIDGV

NO. (Ubiquitin SCEKSMSQVDVDSGIENMEVDENDRREKRSLSDKEPSSGPEVSEEQALQLVCKIF

28 conjugation RVSWKDRDRDVIFLSSLSAQFKQNPKEVFSDFKDLIGQILMEVLMMSTQTRDENP factor E4 B) FASLTATSQPIAAAARSPDRNLLLNTGSNPGTSPMFCSVASFGASSLSSLYESSPAP

>sp|095155|UB TPSFWSSVPVMGPSLASPSRAASQLAVPSTPLSPHSAASGTAAGSQPSSPRYRPY

E4B_HUMAN TVTHPWASSGVSILSSSPSPPALASSPQAVPASSSRQRPSSTGPPLPPASPSATSRR

Ubiquitin PSSLRISPSLGASGGASNWDSYSDHFTIETCKETDMLNYLIECFDRVGIEEKKAPKM conjugation CSQPAVSQLLSNIRSQCISHTALVLQGSLTQPRSLQQPSFLVPYMLCRNLPYGFIQE factor E4 B LVRTTHQDEEVFKQIFIPILQGLALAAKECSLDSDYFKYPLMALGELCETKFGKTHP

VCNLVASLRLWLPKSLSPGCGRELQRLSYLGAFFSFSVFAEDDVKVVEKYFSGPAIT

LENTRVVSQSLQHYLELGRQELFKILHSILLNGETREAALSYMAAVVNANMKKAQ

MQTDDRLVSTDGFMLNFLWVLQQLSTKIKLETVDPTYIFHPRCRITLPNDETRVN

ATMEDVNDWLTELYGDQPPFSEPKFPTECFFLTLHAHHLSILPSCRRYIRRLRAIRE

LNRTVEDLKNNESQWKDSPLATRHREMLKRCKTQLKKLVRCKACADAGLLDESFL

RRCLNFYGLLIQLLLRILDPAYPDITLPLNSDVPKVFAALPEFYVEDVAEFLFFIVQYS

PQALYEPCTQDIVMFLVVMLCNQNYIRNPYLVAKLVEVMFMTNPAVQPRTQKF

FEMIENHPLSTKLLVPSLMKFYTDVEHTGATSEFYDKFTIRYHISTIFKSLWQNIAHH

GTFMEEFNSGKQFVRYINMLINDTTFLLDESLESLKRIHEVQEEMKNKEQWDQLP

RDQQQARQSQLAQDERVSRSYLALATETVDMFHILTKQVQKPFLRPELGPRLAA

MLNFNLQQLCGPKCRDLKVENPEKYGFEPKKLLDQLTDIYLQLDCARFAKAIADD

QRSYSKELFEEVISKMRKAGIKSTIAIEKFKLLAEKVEEIVAKNARAEIDYSDAPDEFR DPLMDTLMTDPVRLPSGTIMDRSIILRHLLNSPTDPFNRQTLTESMLEPVPELKEQ IQAWMREKQNSDH

TRIP12 (Thyroid MSNRPNNNPGGSLRRSQRNTAGAQPQDDSIGGRSCSSSSAVIVPQPEDPDRAN

SEQID

Hormone TSERQKTGQVPKKDNSRGVKRSASPDYNRTNSPSSAKKPKALQHTESPSETNKPH

NO. Receptor SKSKKRHLDQEQQLKSAQSPSTSKAHTRKSGATGGSRSQKRKRTESSCVKSGSGS

29 Interactor 12) ESTGAEERSAKPTKLASKSATSAKAGCSTITDSSSAASTSSSSSAVASASSTVPPGAR >sp|Q14669|TR VKQGKDQNKARRSRSASSPSPRRSSREKEQSKTGGSSKFDWAARFSPKVSLPKTK IPC_HUMAN E3 LSLPGSSKSETSKPGPSGLQAKLASLRKSTKKRSESPPAELPSLRRSTRQKTTGSCAS ubiquitin- TSRRGSGLGKRGAAEARRQEKMADPESNQEAVNSSAARTDEAPQGAAGAVGM protein ligase TTSGESESDDSEMGRLQALLEARGLPPHLFGPLGPRMSQLFHRTIGSGASSKAQQ TRIP12 LLQGLQASDESQQLQAVIEMCQLLVMGNEETLGGFPVKSVVPALITLLQMEHNF

DIMNHACRALTYMMEALPRSSAVVVDAIPVFLEKLQVIQCIDVAEQALTALEMLS

RRHSKAILQAGGLADCLLYLEFFSINAQRNALAIAANCCQSITPDEFHFVADSLPLLT

QRLTHQDKKSVESTCLCFARLVDNFQHEENLLQQVASKDLLTNVQQLLVVTPPILS

SGMFIMVVRMFSLMCSNCPTLAVQLMKQNIAETLHFLLCGASNGSCQEQIDLVP

RSPQELYELTSLICELMPCLPKEGIFAVDTMLKKGNAQNTDGAIWQWRDDRGLW

HPYNRIDSRIIEQINEDTGTARAIQRKPNPLANSNTSGYSESKKDDARAQLMKEDP

ELAKSFIKTLFGVLYEVYSSSAGPAVRHKCLRAILRIIYFADAELLKDVLKNHAVSSHI

ASMLSSQDLKIVVGALQMAEILMQKLPDIFSVYFRREGVMHQVKHLAESESLLTS

PPKACTNGSGSMGSTTSVSSGTATAATHAAADLGSPSLQHSRDDSLDLSPQGRLS

DVLKRKRLPKRGPRRPKYSPPRDDDKVDNQAKSPTTTQSPKSSFLASLNPKTWGR

LSTQSNSNNIEPARTAGGSGLARAASKDTISNNREKIKGWIKEQAHKFVERYFSSE

NMDGSNPALNVLQRLCAATEQLNLQVDGGAECLVEIRSIVSESDVSSFEIQHSGF

VKQLLLYLTSKSEKDAVSREIRLKRFLHVFFSSPLPGEEPIGRVEPVGNAPLLALVHK

MNNCLSQMEQFPVKVHDFPSGNGTGGSFSLNRGSQALKFFNTHQLKCQLQRHP

DCANVKQWKGGPVKIDPLALVQAIERYLVVRGYGRVREDDEDSDDDGSDEEIDE

SLAAQFLNSGNVRHRLQFYIGEHLLPYNMTVYQAVRQFSIQAEDERESTDDESNP

LGRAGIWTKTHTIWYKPVREDEESNKDCVGGKRGRAQTAPTKTSPRNAKKHDEL

WHDGVCPSVSNPLEVYLIPTPPENITFEDPSLDVILLLRVLHAISRYWYYLYDNAMC

KEIIPTSEFINSKLTAKANRQLQDPLVIMTGNIPTWLTELGKTCPFFFPFDTRQMLF

YVTAFDRDRAMQRLLDTNPEINQSDSQDSRVAPRLDRKKRTVNREELLKQAESV

MQDLGSSRAMLEIQYENEVGTGLGPTLEFYALVSQELQRADLGLWRGEEVTLSN

PKGSQEGTKYIQNLQGLFALPFGRTAKPAHIAKVKMKFRFLGKLMAKAIMDFRLV

DLPLGLPFYKWMLRQETSLTSHDLFDIDPVVARSVYHLEDIVRQKKRLEQDKSQTK

ESLQYALETLTMNGCSVEDLGLDFTLPGFPNIELKKGGKDIPVTIHNLEEYLRLVIF

WALNEGVSRQFDSFRDGFESVFPLSHLQYFYPEELDQLLCGSKADTWDAKTLME

CCRPDHGYTHDSRAVKFLFEILSSFDNEQQRLFLQFVTGSPRLPVGGFRSLNPPLTI

VRKTFESTENPDDFLPSVMTCVNYLKLPDYSSIEIMREKLLIAAREGQQSFHLS

SMURF2 (SMAD MSNPGGRRNGPVKLRLTVLCAKNLVKKDFFRLPDPFAKVVVDGSGQCHSTDTVK

SEQID

Specific E3 NTLDPKWNQHYDLYIGKSDSVTISVWNHKKIHKKQGAGFLGCVRLLSNAINRLKD

NO. Ubiquitin TGYQRLDLCKLGPNDNDTVRGQIVVSLQSRDRIGTGGQVVDCSRLFDNDLPDG

30 Protein Ligase 2) WEERRTASGRIQYLNHITRTTQWERPTRPASEYSSPGRPLSCFVDENTPISGTNGA >sp|Q9HAU4|S TCGQSSDPRLAERRVRSQRHRNYMSRTHLHTPPDLPEGYEQRTTQQGQVYFLHT MUF2_HUMAN QTGVSTWHDPRVPRDLSNINCEELGPLPPGWEIRNTATGRVYFVDHNNRTTQFT E3 ubiquitin- DPRLSANLHLVLNRQNQLKDQQQQQVVSLCPDDTECLTVPRYKRDLVQKLKILR protein ligase QELSQQQPQAGHCRIEVSREEIFEESYRQVMKMRPKDLWKRLMIKFRGEEGLDY SMURF2 GGVAREWLYLLSHEMLNPYYGLFQYSRDDIYTLQINPDSAVNPEHLSYFHFVGRI

MGMAVFHGHYIDGGFTLPFYKQLLGKSITLDDMELVDPDLHNSLVWILENDITGV

LDHTFCVEHNAYGEIIQHELKPNGKSIPVNEENKKEYVRLYVNWRFLRGIEAQFLA

LQKGFNEVIPQHLLKTFDEKELELIICGLGKIDVNDWKVNTRLKHCTPDSNIVKWF

WKAVEFFDEERRARLLQFVTGSSRVPLQGFKALQGAAGPRLFTIHQIDACTNNLP

KAHTCFNRIDIPPYESYEKLYEKLLTAIEETCGFAVE GZMB MQPILLLLAFLLLPRADAGEIIGGHEAKPHSRPYMAYLMIWDQKSLKRCGGFLIRD

SEQID

(Granzyme B) DFVLTAAHCWGSSINVTLGAHNIKEQEPTQQFIPVKRPIPHPAYNPKNFSNDIMLL

NO. >sp|P10144|GR QLERKAKRTRAVQPLRLPSNKAQVKPGQTCSVAGWGQTAPLGKHSHTLQEVKM

31 AB_HUMAN TVQEDRKCESDLRHYYDSTIELCVGDPEIKKTSFKGDSGGPLVCNKVAQGIVSYGR Granzyme B NNGMPPRACTKVSSFVHWIKKTMKRY

UPF1 (Regulator MSVEAYGPSSQTLTFLDTEEAELLGADTQGSEFEFTDFTLPSQTQTPPGGPGGPG

SEQID

of nonsense GGGAGGPGGAGAGAAAGQLDAQVGPEGILQNGAVDDSVAKTSQLLAELNFEE NO. transcripts 1) DEEDTYYTKDLPIHACSYCGIHDPACVVYCNTSKKWFCNGRGNTSGSHIVNHLVR

32 >sp|Q92900|RE AKCKEVTLHKDGPLGETVLECYNCGCRNVFLLGFIPAKADSVVVLLCRQPCASQSS NT1_HUMAN LKDINWDSSQWQPLIQDRCFLSWLVKIPSEQEQLRARQITAQQINKLEELWKENP Regulator of SATLEDLEKPGVDEEPQHVLLRYEDAYQYQNIFGPLVKLEADYDKKLKESQTQDNI nonsense TVRWDLGLNKKRIAYFTLPKTDSGNEDLVIIWLRDMRLMQGDEICLRYKGDLAPL transcripts 1 WKGIGHVIKVPDNYGDEIAIELRSSVGAPVEVTHNFQVDFVWKSTSFDRMQSAL

KTFAVDETSVSGYIYHKLLGHEVEDVIIKCQLPKRFTAQGLPDLNHSQVYAVKTVL

QRPLSLIQGPPGTGKTVTSATIVYHLARQGNGPVLVCAPSNIAVDQLTEKIHQTGL

KVVRLCAKSREAIDSPVSFLALHNQIRNMDSMPELQKLQQLKDETGELSSADEKR

YRALKRTAERELLMNADVICCTCVGAGDPRLAKMQFRSILIDESTQATEPECMVP

VVLGAKQLILVGDHCQLGPVVMCKKAAKAGLSQSLFERLVVLGIRPIRLQVQYRM

HPALSAFPSNIFYEGSLQNGVTAADRVKKGFDFQWPQPDKPMFFYVTQGQEEIA

SSGTSYLNRTEAANVEKITTKLLKAGAKPDQIGIITPYEGQRSYLVQYMQFSGSLHT

KLYQEVEIASVDAFQGREKDFIILSCVRANEHQGIGFLNDPRRLNVALTRARYGVII

VGNPKALSKQPLWNHLLNYYKEQKVLVEGPLNNLRESLMQFSKPRKLVNTINPG

ARFMTTAMYDAREAIIPGSVYDRSSQGRPSSMYFQTHDQIGMISAGPSHVAAM

NIPIPFNLVMPPMPPPGYFGQANGPAAGRGTPKGKTGRGGRQKNRFGLPGPSQ

TNLPNSQASQDVASQPFSQGALTQGYISMSQPSQMSQPGLSQPELSQDSYLGDE

F KSQI D VALSQDSTYQG E RAYQHGGVTG LSQY

PPP1CB MADGELNVDSLITRLLEVRGCRPGKIVQMTEAEVRGLCIKSREIFLSQPILLELEAPL

SEQID

(Serine/threoni KICGDIHGQYTDLLRLFEYGGFPPEANYLFLGDYVDRGKQSLETICLLLAYKIKYPEN NO. ne-protein FFLLRGNHECASINRIYGFYDECKRRFNIKLWKTFTDCFNCLPIAAIVDEKIFCCHGG

33 phosphatase LSPDLQSMEQIRRIMRPTDVPDTGLLCDLLWSDPDKDVQGWGENDRGVSFTFG

PPl-beta ADVVSKFLNRHDLDLICRAHQVVEDGYEFFAKRQLVTLFSAPNYCGEFDNAGGM catalytic MSVDETLMCSFQILKPSEKKAKYQYGGLNSGRPVTPPRTANPPKKR subunit)

>sp|P62140|PP

1B_HUMAN

Serine/threonin

e-protein

phosphatase

PPl-beta

catalytic subunit

ATP5D (ATP MLPAALLRRPGLGRLVRHARAYAEAAAAPAAASGPNQMSFTFASPTQVFFNGA

SEQID

synthase NVRQVDVPTLTGAFGILAAHVPTLQVLRPGLVVVHAEDGTTSKYFVSSGSIAVNA

NO. subunit delta, DSSVQLLAEEAVTLDMLDLGAAKANLEKAQAELVGTADEATRAEIQIRIEANEALV

34 mitochondrial) KALE

>sp 1 P300491 AT

PD_HUMAN

ATP synthase

subunit delta,

mitochondrial

EIF2A MAPSTPLLTVRGSEGLYMVNGPPHFTESTVFPRESGKNCKVCIFSKDGTLFAWGN

SEQID

(Eukaryotic GEKVNIISVTNKGLLHSFDLLKAVCLEFSPKNTVLATWQPYTTSKDGTAGIPNLQLY NO. translation DVKTGTCLKSFIQKKMQNWCPSWSEDETLCARNVNNEVHFFENNNFNTIANKL initiation factor HLQKINDFVLSPGPQPYKVAVYVPGSKGAPSFVRLYQYPNFAGPHAALANKSFFK

35

2A) ADKVTMLWNKKATAVLVIASTDVDKTGASYYGEQTLHYIATNGESAVVQLPKNG

>sp|Q9BY44|EI PIYDVVWNSSSTEFCAVYGFMPAKATIFNLKCDPVFDFGTGPRNAAYYSPHGHIL

F2A_HUMAN VLAGFGNLRGQMEVWDVKNYKLISKPVASDSTYFAWCPDGEHILTATCAPRLRV

Eukaryotic NNGYKIWHYTGSILHKYDVPSNAELWQVSWQPFLDGIFPAKTITYQAVPSEVPNE translation EPKVATAYRPPALRNKPITNSKLHEEEPPQNMKPQSGNDKPLSKTALKNQRKHEA initiation factor KKAAKQEARSDKSPDLAPTPAPQSTPRNTVSQSISGDPEIDKKIKNLKKKLKAIEQL

2A KEQAATGKQLEKNQLEKIQKETALLQELEDLELGI

EIF5B MGKKQKNKSEDSTKDDIDLDALAAEIEGAGAAKEQEPQKSKGKKKKEKKKQDFD

SEQID

(Eukaryotic EDDILKELEELSLEAQGIKADRETVAVKPTENNEEEFTSKDKKKKGQKGKKQSFDD

NO. translation NDSEELEDKDSKSKKTAKPKVEMYSGSDDDDDFNKLPKKAKGKAQKSNKKWDG

36 initiation factor SEEDEDNSKKIKERSRINSSGESGDESDEFLQSRKGQKKNQKNKPGPNIESGNEDD 5B) DASFKIKTVAQKKAEKKERERKKRDEEKAKLRKLKEKEELETGKKDQSKQKESQRKF

>sp| 060841 |IF2 EEETVKSKVTVDTGVIPASEEKAETPTAAEDDNEGDKKKKDKKKKKGEKEEKEKEK

P_HUMAN KKGPSKATVKAMQEALAKLKEEEERQKREEEERIKRLEELEAKRKEEERLEQEKRER

Eukaryotic KKQKEKERKERLKKEGKLLTKSQREARARAEATLKLLQAQGVEVPSKDSLPKKRPIY translation EDKKRKKIPQQLESKEVSESMELCAAVEVMEQGVPEKEETPPPVEPEEEEDTEDA initiation factor GLDDWEAMASDEETEKVEGNKVHIEVKENPEEEEEEEEEEEEDEESEEEEEEEGES

5B EGSEGDEEDEKVSDEKDSGKTLDKKPSKEMSSDSEYDSDDDRTKEERAYDKAKRRI

EKRRLEHSKNVNTEKLRAPIICVLGHVDTGKTKILDKLRHTHVQDGEAGGITQQIG

ATNVPLEAINEQTKMIKNFDRENVRIPGMLIIDTPGHESFSNLRNRGSSLCDIAILV

VDIMHGLEPQTIESINLLKSKKCPFIVALNKIDRLYDWKKSPDSDVAATLKKQKKNT

KDEFEERAKAIIVEFAQQGLNAALFYENKDPRTFVSLVPTSAHTGDGMGSLIYLLVE

LTQTMLSKRLAHCEELRAQVMEVKALPGMGTTIDVILINGRLKEGDTIIVPGVEGP

IVTQIRGLLLPPPMKELRVKNQYEKHKEVEAAQGVKILGKDLEKTLAGLPLLVAYKE

DEIPVLKDELIHELKQTLNAIKLEEKGVYVQASTLGSLEALLEFLKTSEVPYAGINIGP

VHKKDVMKASVMLEHDPQYAVILAFDVRIERDAQEMADSLGVRIFSAEIIYHLFD

AFTKYRQDYKKQKQEEFKHIAVFPCKIKILPQYIFNSRDPIVMGVTVEAGQVKQGT

PMCVPSKNFVDIGIVTSIEINHKQVDVAKKGQEVCVKIEPIPGESPKMFGRHFEAT

DILVSKISRQSIDALKDWFRDEMQKSDWQLIVELKKVFEII

MAP4K1 MDVVDPDIFNRDPRDHYDLLQRLGGGTYGEVFKARDKVSGDLVALKMVKMEPD

SEQID

(Mitogen- DDVSTLQKEILILKTCRHANIVAYHGSYLWLQKLWICMEFCGAGSLQDIYQVTGSL

NO. activated SELQISYVCREVLQGLAYLHSQKKIHRDIKGANILINDAGEVRLADFGISAQIGATLA

37 protein kinase RRLSFIGTPYWMAPEVAAVALKGGYNELCDIWSLGITAIELAELQPPLFDVHPLRV 1) LFLMTKSGYQPPRLKEKGKWSAAFHNFIKVTLTKSPKKRPSATKMLSHQLVSQPG

>sp|Q92918|M LNRGLILDLLDKLKNPGKGPSIGDIEDEEPELPPAIPRRIRSTHRSSSLGIPDADCCRR 4K1_HUMAN HMEFRKLRGMETRPPANTARLQPPRDLRSSSPRKQLSESSDDDYDDVDIPTPAED Mitogen- TPPPLPPKPKFRSPSDEGPGSMGDDGQLSPGVLVRCASGPPPNSPRPGPPPSTSS activated PHLTAHSEPSLWNPPSRELDKPPLLPPKKEKMKRKGCALLVKLFNGCPLRIHSTAA protein kinase WTHPSTKDQHLLLGAEEGIFILNRNDQEATLEMLFPSRTTWVYSINNVLMSLSGK kinase kinase TPHLYSHSILGLLERKETRAGNPIAHISPHRLLARKNMVSTKIQDTKGCRACCVAEG kinase 1 ASSGGPFLCGALETSVVLLQWYQPMNKFLLVRQVLFPLPTPLSVFALLTGPGSELP

AVCIGVSPGRPGKSVLFHTVRFGALSCWLGEMSTEHRGPVQVTQVEEDMVMVL

MDGSVKLVTPEGSPVRGLRTPEIPMTEAVEAVAMVGGQLQAFWKHGVQVWAL

GSDQLLQELRDPTLTFRLLGSPRLECSGTISPHCNLLLPGSSNSPASASRVAGITGL

ANXA4 (Annexin MATKGGTVKAASGFNAMEDAQTLRKAMKGLGTDEDAIISVLAYRNTAQRQEIRT

SEQID IV) AYKSTIGRDLIDDLKSELSGNFEQVIVGMMTPTVLYDVQELRRAMKGAGTDEGCL

NO. >sp|P09525|AN IEILASRTPEEIRRISQTYQQQYGRSLEDDIRSDTSFMFQRVLVSLSAGGRDEGNYL

38 XA4_HUMAN DDALVRQDAQDLYEAGEKKWGTDEVKFLTVLCSRNRNHLLHVFDEYKRISQKDIE Annexin A4 QSIKSETSGSFEDALLAIVKCMRNKSAYFAEKLYKSMKGLGTDDNTLIRVMVSRAEI

DMLDIRAHFKRLYGKSLYSFIKGDTSGDYRKVLLVLCGGDD

LGALS3BP MTPPRLFWVWLLVAGTQGVNDGDMRLADGGATNQGRVEIFYRGQWGTVCD

SEQID (Galectin-3- NLWDLTDASVVCRALGFENATQALGRAAFGQGSGPIMLDEVQCTGTEASLADC

NO.

binding protein) KSLGWLKSNCRHERDAGVVCTNETRSTHTLDLSRELSEALGQIFDSQRGCDLSISV

39 >sp|Q08380|LG NVQGEDALGFCGHTVILTANLEAQALWKEPGSNVTMSVDAECVPMVRDLLRYF 3BP_HUMAN YSRRIDITLSSVKCFHKLASAYGARQLQGYCASLFAILLPQDPSFQMPLDLYAYAVA Galectin-3- TGDALLEKLCLQFLAWNFEALTQAEAWPSVPTDLLQLLLPRSDLAVPSELALLKAV binding protein DTWSWGERASHEEVEGLVEKIRFPMMLPEELFELQFNLSLYWSHEALFQKKTLQ

ALEFHTVPFQLLARYKGLNLTEDTYKPRIYTSPTWSAFVTDSSWSARKSQLVYQSR

RGPLVKYSSDYFQAPSDYRYYPYQSFQTPQHPSFLFQDKRVSWSLVYLPTIQSCW

NYGFSCSSDELPVLGLTKSGGSDRTIAYENKALMLCEGLFVADVTDFEGWKAAIPS

ALDTNSSKSTSSFPCPAGHFNGFRTVIRPFYLTNSSGVD

MOV10 (RISC MPSKFSCRQLREAGQCFESFLVVRGLDMETDRERLRTIYNRDFKISFGTPAPGFSS

SEQID

complex RNA MLYGMKIANLAYVTKTRVRFFRLDRWADVRFPEKRRMKLGSDISKHHKSLLAKIF

NO. helicase) YDRAEYLHGKHGVDVEVQGPHEARDGQLLIRLDLNRKEVLTLRLRNGGTQSVTLT

40 >sp|Q9HCEl|M HLFPLCRTPQFAFYNEDQELPCPLGPGECYELHVHCKTSFVGYFPATVLWELLGPG

OV10_HUMAN ESGSEGAGTFYIARFLAAVAHSPLAAQLKPMTPFKRTRITGNPVVTNRIEEGERPD

Putative RAKGYDLELSMALGTYYPPPRLRQLLPMLLQGTSIFTAPKEIAEIKAQLETALKWRN helicase MOV- YEVKLRLLLHLEELQMEHDIRHYDLESVPMTWDPVDQNPRLLTLEVPGVTESRPS 10 VLRGDHLFALLSSETHQEDPITYKGFVHKVELDRVKLSFSMSLLSRFVDGLTFKVNF

TFNRQPLRVQHRALELTGRWLLPMLFPVAPRDVPLLPSDVKLKLYDRSLESNPEQL

QAMRHIVTGTTRPAPYIIFGPPGTGKTVTLVEAIKQVVKHLPKAHILACAPSNSGA

DLLCQRLRVHLPSSIYRLLAPSRDIRMVPEDIKPCCNWDAKKGEYVFPAKKKLQEY

RVLITTLITAGRLVSAQFPIDHFTHIFIDEAGHCMEPESLVAIAGLMEVKETGDPGG

QLVLAGDPRQLGPVLRSPLTQKHGLGYSLLERLLTYNSLYKKGPDGYDPQFITKLLR

NYRSHPTILDIPNQLYYEGELQACADVVDRERFCRWAGLPRQGFPIIFHGVMGKD

EREGNSPSFFNPEEAATVTSYLKLLLAPSSKKGKARLSPRSVGVISPYRKQVEKIRYCI

TKLDRELRGLDDIKDLKVGSVEEFQGQERSVILISTVRSSQSFVQLDLDFNLGFLKN

PKRFNVAVTRAKALLIIVGNPLLLGHDPDWKVFLEFCKENGGYTGCPFPAKLDLQ

QGQNLLQGLSKLSPSTSGPHSHDYLPQEREGEGGLSLQVEPEWRNEL

PDHB (pyruvate MAAVSGLVRRPLREVSGLLKRRFHWTAPAALQVTVRDAINQGMDEELERDEKVF

SEQID

dehydrogenase LLGEEVAQYDGAYKVSRGLWKKYGDKRIIDTPISEMGFAGIAVGAAMAGLRPICE

NO. (lipoamide) FMTFNFSMQAIDQVINSAAKTYYMSGGLQPVPIVFRGPNGASAGVAAQHSQCF

41 beta) AAWYGHCPGLKVVSPWNSEDAKGLIKSAIRDNNPVVVLENELMYGVPFEFPPEA

>sp|P11177|OD QSKDFLIPIGKAKIERQGTHITVVSHSRPVGHCLEAAAVLSKEGVECEVINMRTIRP

PB_HUMAN MDMETIEASVMKTNHLVTVEGGWPQFGVGAEICARIMEGPAFNFLDAPAVRVT

Pyruvate GADVPMPYAKILEDNSIPQVKDIIFAIKKTLNI

dehydrogenase

El component

subunit beta,

mitochondrial

PPFIA1 (Protein MMCEVMPTISEAEGPPGGGGGHGSGSPSQPDADSHFEQLMVSMLEERDRLLD

SEQID

Tyrosine TLRETQETLALTQGKLHEVGHERDSLQRQLNTALPQEFAALTKELNVCREQLLERE

NO. Phosphatase EEIAELKAERNNTRLLLEHLECLVSRHERSLRMTVVKRQAQSPAGVSSEVEVLKALK

42 Receptor Type F SLFEHHKALDEKVRERLRVALERCSLLEEELGATHKELMILKEQNNQKKTLTDGVL

Polypeptide- DINHEQENTPSTSGKRSSDGSLSHEEDLAKVIELQEIISKQSREQSQMKERLASLSS

Interacting HVTELEEDLDTARKDLIKSEEMNTKLQRDVREAMAQKEDMEERITTLEKRYLAAQ

Protein REATSVHDLNDKLENEIANKDSMHRQTEDKNRQLQERLELAEQKLQQTLRKAETL

>sp|Q13136|LIP PEVEAELAQRVAALSKAEERHGNIEERLRQMEAQLEEKNQELQRARQREKMNEE

A1_HUMAN HNKRLSDTVDKLLSESNERLQLHLKERMAALEDKNSLLREVESAKKQLEETQHDK

Liprin-alpha-1 DQLVLNIEALRAELDHMRLRGASLHHGRPHLGSVPDFRFPMADGHTDSYSTSAV

LRRPQKGRLAALRDEPSKVQTLNEQDWERAQQASVLANVAQAFESDADVSDGE

DDRDTLLSSVDLLSPSGQADAHTLAMMLQEQLDAINKEIRLIQEEKENTEQRAEEI

ESRVGSGSLDNLGRFRSMSSIPPYPASSLASSSPPGSGRSTPRRIPHSPAREVDRLG VMTLLPPSREEVRDDKTTIKCETSPPSSPRALRLDRLHKGALHTVSHEDIRDIRNST

GSQDGPVSNPSSSNSSQDSLHKAPKKKGIKSSIGRLFGKKEKGRPGQTGKEALGQ

AGVSETDNSSQDALGLSKLGGQAEKNRKLQKKHELLEEARRQGLPFAQWDGPTV

VVWLELWVGMPAWYVAACRANVKSGAIMSALSDTEIQREIGISNPLHRLKLRLAI

QEIMSLTSPSAPPTSRTTLAYGDMNHEWIGNEWLPSLGLPQYRSYFMECLVDAR

MLDHLTKKDLRGQLKMVDSFHRNSFQCGIMCLRRLNYDRKELERKREESQSEIKD

VLVWSNDRVIRWILSIGLKEYANNLIESGVHGALLALDETFDFSALALLLQIPTQNT

QARAVLEREFNNLLVMGTDRRFDEDDDKSFRRAPSWRKKFRPKDIRGLAAGSAE

TLPANFRVTSSMSSPSMQPKKMQMDGNVSGTQRLDSATVRTYSC

CHMP4B MSVFGKLFGAGGGKAGKGGPTPQEAIQRLRDTEEMLSKKQEFLEKKIEQELTAAK

SEQID

(Charged KHGTKNKRAALQALKRKKRYEKQLAQIDGTLSTIEFQREALENANTNTEVLKNMG

NO. Multivesicular YAAKAMKAAHDNMDIDKVDELMQDIADQQELAEEISTAISKPVGFGEEFDEDEL

43 Body Protein MAELEELEQEELDKNLLEISGPETVPLPNVPSIALPSKPAKKKEEEDDDMKELENW 4B) AGSM

>sp|Q9H444|C

HM4B_HUMAN

Charged

multivesicular

body protein 4b

Alpha-lCLICl MAEEQPQVELFVKAGSDGAKIGNCPFSQRLFMVLWLKGVTFNVTTVDTKRRTET

SEQID

(Chloride VQKLCPGGQLPFLLYGTEVHTDTNKIEEFLEAVLCPPRYPKLAALNPESNTAGLDIF

NO. Intracellular AKFSAYIKNSNPALNDNLEKGLLKALKVLDNYLTSPLPEEVDETSAEDEGVSQRKFL

44 Channel 1) DGNELTLADCNLLPKLHIVQVVCKKYRGFTIPEAFRGVHRYLSNAYAREEFASTCP

>sp| 0002991 CLI DDEEIELAYEQVAKALK

C1_HUMAN

Chloride

intracellular

channel protein

1

RARA (Retinoic MASNSSSCPTPGGGHLNGYPVPPYAFFFPPMLGGLSPPGALTTLQHQLPVSGYST

SEQID

Acid Receptor, PSPATIETQSSSSEEIVPSPPSPPPLPRIYKPCFVCQDKSSGYHYGVSACEGCKGFFR

NO. Alpha) RSIQKNMVYTCHRDKNCIINKVTRNRCQYCRLQKCFEVGMSKESVRNDRNKKKK

45 >sp|P10276|RA EVPKPECSESYTLTPEVGELIEKVRKAHQETFPALCQLGKYTTNNSSEQRVSLDIDL RA_HUMAN WDKFSELSTKCIIKTVEFAKQLPGFTTLTIADQITLLKAACLDILILRICTRYTPEQDT Retinoic acid MTFSDGLTLNRTQMHNAGFGPLTDLVFAFANQLLPLEMDDAETGLLSAICLICGD receptor alpha RQDLEQPDRVDMLQEPLLEALKVYVRKRRPSRPHMFPKMLMKITDLRSISAKGAE

RVITLKMEIPGSMPPLIQEMLENSEGLDTLSGQPGGGGRDGGGLAPPPGSCSPSL

SPSSNRSSPATHSP

MATR3 (Matrin MS KS FQQSS LS RDSQGHGRD LSAAG 1 G LLAAATQS LS M PAS LG R M NQGTAR LAS

SEQID

3) LMNLGMSSSLNQQGAHSALSSASTSSHNLQSIFNIGSRGPLPLSSQHRGDADQAS

NO. >sp|P43243|M NILASFGLSARDLDELSRYPEDKITPENLPQILLQLKRRRTEEGPTLSYGRDGRSATR

46 ATR3_HUMAN EPPYRVPRDDWEEKRHFRRDSFDDRGPSLNPVLDYDHGSRSQESGYYDRMDYE

Matrin-3 DDRLRDGERCRDDSFFGETSHNYHKFDSEYERMGRGPGPLQERSLFEKKRGAPPS

SNIEDFHGLLPKGYPHLCSICDLPVHSNKEWSQHINGASHSRRCQLLLEIYPEWNP

DNDTGHTMGDPFMLQQSTNPAPGILGPPPPSFHLGGPAVGPRGNLGAGNGNL

QGPRHMQKGRVETSRVVHIMDFQRGKNLRYQLLQLVEPFGVISNHLILNKINEAF

IEMATTEDAQAAVDYYTTTPALVFGKPVRVHLSQKYKRIKKPEGKPDQKFDQKQE

LGRVIHLSNLPHSGYSDSAVLKLAEPYGKIKNYILMRMKSQAFIEMETREDAMAM

VDHCLKKALWFQGRCVKVDLSEKYKKLVLRIPNRGIDLLKKDKSRKRSYSPDGKES

PSDKKSKTDGSQKTESSTEGKEQEEKSGEDGEKDTKDDQTEQEPNMLLESEDELL

VDEEEAAALLESGSSVGDETDLANLGDVASDGKKEPSDKAVKKDGSASAAAKKKL KKVDKIEELDQENEAALENGIKNEENTEPGAESSENADDPNKDTSENADGQSDE

NKDDYTIPDEYRIGPYQPNVPVGIDYVIPKTGFYCKLCSLFYTNEEVAKNTHCSSLP HYQKLKKFLNKLAEERRQKKET

GTPBP1 (GTP- MATERSRSAMDSPVPASMFAPEPSSPGAARAAAAAARLHGGFDSDCSEDGEAL

SEQID

binding protein NGEPELDLTSKLVLVSPTSEQYDSLLRQMWERMDEGCGETIYVIGQGSDGTEYGL

NO.

1) SEADMEASYATVKSMAEQIEADVILLRERQEAGGRVRDYLVRKRVGDNDFLEVR

47 >sp| 000178 |GT VAVVGNVDAGKSTLLGVLTHGELDNGRGFARQKLFRHKHEIESGRTSSVGNDILG PB1_HUMAN FDSEGNVVNKPDSHGGSLEWTKICEKSTKVITFIDLAGHEKYLKTTVFGMTGHLPD GTP-binding FCMLMVGSNAGIVGMTKEHLGLALALNVPVFVVVTKIDMCPANILQETLKLLQRL protein 1 LKSPGCRKIPVLVQSKDDVIVTASNFSSERMCPIFQISNVTGENLDLLKMFLNLLSP

RTSYREEEPAEFQIDDTYSVPGVGTVVSGTTLRGLIKLNDTLLLGPDPLGNFLSIAVK

SIHRKRMPVKEVRGGQTASFALKKIKRSSIRKGMVMVSPRLNPQASWEFEAEILV

LHHPTTISPRYQAMVHCGSIRQTATILSMDKDCLRTGDKATVHFRFIKTPEYLHID

QRLVFREGRTKAVGTITKLLQTTNNSPMNSKPQQIKMQSTKKGPLTKRDEGGPS

GGPAVGAPPPGDEASSVGAGQPAASSNLQPQPKPSSGGRRRGGQRHKVKSQG

ACVTPASGC

SMC5 MATPSKKTSTPSPQPSKRALPRDPSSEVPSKRKNSAPQLPLLQSSGPFVEGSIVRIS

SEQID

(Structural MENFLTYDICEVSPGPHLNMIVGANGTGKSSIVCAICLGLAGKPAFMGRADKVGF

NO. maintenance of FVKRGCSRGMVEIELFRASGNLVITREIDVAKNQSFWFINKKSTTQKIVEEKVAAL

48 chromosomes NIQVGNLCQFLPQDKVGEFAKLSKIELLEATEKSIGPPEMHKYHCELKNLREKEKQL protein 5) ETSCKEKTEYLQKMVQRNERYKQDVERFYERKRHLDLIEMLEAKRPWVEYENVR

>sp|Q8IY18|SM QEYEEVKLVRDRVKEEVRKLKEGQIPVTCRIEEMENERHNLEARIKEKATDIKEASQ

C5_HUMAN KCKQKQDVIERKDKHIEELQQALIVKQNEELDRQRRIGNTRKMIEDLQNELKTTEN

Structural CENLQPQIDAITNDLRRIQDEKALCEGEIIDKRRERETLEKEKKSVDDHIVRFDNLM maintenance of NQKEDKLRQRFRDTYDAVLWLRNNRDKFKQRVCEPIMLTINMKDNKNAKYIEN chromosomes HIPSNDLRAFVFESQEDMEVFLKEVRDNKKLRVNAVIAPKSSYADKAPSRSLNELK protein 5 QYGFFSYLRELFDAPDPVMSYLCCQYHIHEVPVGTEKTRERIERVIQETRLKQIYTA

EEKYVVKTSFYSNKVISSNTSLKVAQFLTVTVDLEQRRHLEEQLKEIHRKLQAVDSG

LIALRETSKHLEHKDNELRQKKKELLERKTKKRQLEQKISSKLGSLKLMEQDTCNLEE

EERKASTKIKEINVQKAKLVTELTNLIKICTSLHIQKVDLILQNTTVISEKNKLESDYM

AASSQLRLTEQHFIELDENRQRLLQKCKELMKRARQVCNLGAEQTLPQEYQTQVP

TIPNGHNSSLPMVFQDLPNTLDEIDALLTEERSRASCFTGLNPTIVQEYTKREEEIE

QLTEELKGKKVELDQYRENISQVKERWLNPLKELVEKINEKFSNFFSSMQCAGEVD

LHTENEEDYDKYGIRIRVKFRSSTQLHELTPHHQSGGERSVSTMLYLMALQELNRC

PFRVVDEINQGMDPINERRVFEMVVNTACKENTSQYFFITPKLLQNLPYSEKMTV

LFVYNGPHMLEPNTWNLKAFQRRRRRITFTQPS

YWHAE (14-3-3 MDDREDLVYQAKLAEQAERYDEMVESMKKVAGMDVELTVEERNLLSVAYKNVI

SEQID

protein epsilon) GARRASWRIISSIEQKEENKGGEDKLKMIREYRQMVETELKLICCDILDVLDKHLIP

NO. >sp|P62258|14 AANTGESKVFYYKMKGDYHRYLAEFATGNDRKEAAENSLVAYKAASDIAMTELP

49 33E_HUMAN PTHPIRLGLALNFSVFYYEILNSPDRACRLAKAAFDDAIAELDTLSEESYKDSTLIMQ 14-3-3 protein LLRDNLTLWTSDMQGDGEEQNKEALQDVEDENQ

epsilon

MARS MRLFVSDGVPGCLPVLAAAGRARGRAEVLISTVGPEDCVVPFLTRPKVPVLQLDS

SEQID

(Methionyl- GNYLFSTSAICRYFFLLSGWEQDDLTNQWLEWEATELQPALSAALYYLVVQGKKG

NO. TRNA EDVLGSVRRALTHIDHSLSRQNCPFLAGETESLADIVLWGALYPLLQDPAYLPEELS

50 Synthetase) ALHSWFQTLSTQEPCQRAAETVLKQQGVLALRPYLQKQPQPSPAEGRAVTNEPE >sp|P56192|SY EEELATLSEEEIAMAVTAWEKGLESLPPLRPQQNPVLPVAGERNVLITSALPYVNN MC_HUMAN VPHLGNIIGCVLSADVFARYSRLRQWNTLYLCGTDEYGTATETKALEEGLTPQEIC Methionine- DKYHIIHADIYRWFNISFDIFGRTTTPQQTKITQDIFQQLLKRGFVLQDTVEQLRCE tRNA ligase, HCARFLADRFVEGVCPFCGYEEARGDQCDKCGKLINAVELKKPQCKVCRSCPVVQ cytoplasmic SSQHLFLDLPKLEKRLEEWLGRTLPGSDWTPNAQFITRSWLRDGLKPRCITRDLK

WGTPVPLEGFEDKVFYVWFDATIGYLSITANYTDQWERWWKNPEQVDLYQFM

AKDNVPFHSLVFPCSALGAEDNYTLVSHLIATEYLNYEDGKFSKSRGVGVFGDMA

QDTGIPADIWRFYLLYIRPEGQDSAFSWTDLLLKNNSELLNNLGNFINRAGMFVS

KFFGGYVPEMVLTPDDQRLLAHVTLELQHYHQLLEKVRIRDALRSILTISRHGNQYI

QVNEPWKRIKGSEADRQRAGTVTGLAVNIAALLSVMLQPYMPTVSATIQAQLQL

PPPACSILLTNFLCTLPAGHQIGTVSPLFQKLENDQIESLRQRFGGGQAKTSPKPAV

VETVTTAKPQQIQALMDEVTKQGNIVRELKAQKADKNEVAAEVAKLLDLKKQLA

VAEGKPPEAPKGKKKK

TAGLN2 MANRGPAYGLSREVQQKIEKQYDADLEQILIQWITTQCRKDVGRPQPGRENFQN

SEQID

(transgelin 2) WLKDGTVLCELINALYPEGQAPVKKIQASTMAFKQMEQISQFLQAAERYGINTTD

NO. >sp|P37802|TA IFQTVDLWEGKNMACVQRTLMNLGGLAVARDDGLFSGDPNWFPKKSKENPRN

51 GL2_HUMAN FSDNQLQEGKNVIGLQMGTNRGASQAGMTGYGMPRQIL

Transgelin-2

STMN1 MASSDIQVKELEKRASGQAFELILSPRSKESVPEFPLSPPKKKDLSLEEIQKKLEAAEE

SEQID

(Stathmin 1) RRKSHEAEVLKQLAEKREHEKEVLQKAIEENNNFSKMAEEKLTHKMEANKENREA

NO. >sp|P16949|ST QMAAKLERLREKDKHIEEVRKNKESKDPADETEAD

52 MN1_HUMAN

Stathmin

SART MGSSKKHRGEKEAAGTTAAAGTGGATEQPPRHREHKKHKHRSGGSGGSGGERR

SEQID

>sp| 043290 |SN KRSRERGGERGSGRRGAEAEARSSTHGRERSQAEPSERRVKREKRDDGYEAAASS

NO. UT1_HUMAN KTSSGDASSLSIEETNKLRAKLGLKPLEVNAIKKEAGTKEEPVTADVINPMALRQRE

53 U4/U6.U5 tri- ELREKLAAAKEKRLLNQKLGKIKTLGEDDPWLDDTAAWIERSRQLQKEKDLAEKR snRNP- AKLLEEMDQEFGVSTLVEEEFGQRRQDLYSARDLQGLTVEHAIDSFREGETMILTL associated KDKGVLQEEEDVLVNVNLVDKERAEKNVELRKKKPDYLPYAEDESVDDLAQQKP protein 1 RSILSKYDEELEGERPHSFRLEQGGTADGLRERELEEIRAKLRLQAQSLSTVGPRLAS

EYLTPEEMVTFKKTKRRVKKIRKKEKEVVVRADDLLPLGDQTQDGDFGSRLRGRG

RRRVSEVEEEKEPVPQPLPSDDTRVENMDISDEEEGGAPPPGSPQVLEEDEAELEL

QKQLEKGRRLRQLQQLQQLRDSGEKVVEIVKKLESRQRGWEEDEDPERKGAIVF

NATSEFCRTLGEIPTYGLAGNREEQEELMDFERDEERSANGGSESDGEENIGWST

VNLDEEKQQQDFSASSTTILDEEPIVNRGLAAALLLCQNKGLLETTVQKVARVKAP

NKSLPSAVYCIEDKMAIDDKYSRREEYRGFTQDFKEKDGYKPDVKIEYVDETGRKL

TPKEAFRQLSHRFHGKGSGKMKTERRMKKLDEEALLKKMSSSDTPLGTVALLQEK

QKAQKTPYIVLSGSGKSMNANTITK

VAV1 (Proto- MELWRQCTHWLIQCRVLPPSHRVTWDGAQVCELAQALRDGVLLCQLLNNLLPH

SEQID

oncogene vav) AINLREVNLRPQMSQFLCLKNIRTFLSTCCEKFGLKRSELFEAFDLFDVQDFGKVIYT

NO. >sp|P15498|VA LSALSWTPIAQNRGIMPFPTEEESVGDEDIYSGLSDQIDDTVEEDEDLYDCVENEE

54 V_HUMAN AEGDEIYEDLMRSEPVSMPPKMTEYDKRCCCLREIQQTEEKYTDTLGSIQQHFLKP

Proto-oncogene LQRFLKPQDIEIIFINIEDLLRVHTHFLKEMKEALGTPGAANLYQVFIKYKERFLVYG vav RYCSQVESASKHLDRVAAAREDVQMKLEECSQRANNGRFTLRDLLMVPMQRVL

KYHLLLQELVKHTQEAMEKENLRLALDAMRDLAQCVNEVKRDNETLRQITNFQL

SIENLDQSLAHYGRPKIDGELKITSVERRSKMDRYAFLLDKALLICKRRGDSYDLKDF

VNLHSFQVRDDSSGDRDNKKWSHMFLLIEDQGAQGYELFFKTRELKKKWMEQF

EMAISNIYPENATANGHDFQMFSFEETTSCKACQMLLRGTFYQGYRCHRCRASA

HKECLGRVPPCGRHGQDFPGTMKKDKLHRRAQDKKRNELGLPKMEVFQEYYGL

PPPPGAIGPFLRLNPGDIVELTKAEAEQNWWEGRNTSTNEIGWFPCNRVKPYVH

GPPQDLSVHLWYAGPMERAGAESILANRSDGTFLVRQRVKDAAEFAISIKYNVEV

KHIKIMTAEGLYRITEKKAFRGLTELVEFYQQNSLKDCFKSLDTTLQFPFKEPEKRTIS

RPAVGSTKYFGTAKARYDFCARDRSELSLKEGDIIKILNKKGQQGWWRGEIYGRV

GWFPANYVEEDYSEYC BCL11B (B-cell MSRRKQGNPQHLSQRELITPEADHVEAAILEEDEGLEIEEPSGLGLMVGGPDPDL

SEQID

lymphoma/leuk LTCGQCQMNFPLGDILVFIEHKRKQCGGSLGACYDKALDKDSPPPSSRSELRKVSE

NO. emia 11B) PVEIGIQVTPDEDDHLLSPTKGICPKQENIAGPCRPAQLPAVAPIAASSHPHSSVITS

55 >sp|Q9C0K0|BC PLRALGALPPCLPLPCCSARPVSGDGTQGEGQTEAPFGCQCQLSGKDEPSSYICTT 11B_HUMAN B- CKQPFNSAWFLLQHAQNTHGFRIYLEPGPASSSLTPRLTIPPPLGPEAVAQSPLM cell NFLGDSNPFNLLRMTGPILRDHPGFGEGRLPGTPPLFSPPPRHHLDPHRLSAEEM lymphoma/leuk GLVAQHPSAFDRVMRLNPMAIDSPAMDFSRRLRELAGNSSTPPPVSPGRGNPM emia 11B HRLLNPFQPSPKSPFLSTPPLPPMPPGGTPPPQPPAKSKSCEFCGKTFKFQSNLIVH

RRSHTGEKPYKCQLCDHACSQASKLKRHMKTHMHKAGSLAGRSDDGLSAASSPE

PGTSELAGEGLKAADGDFRHHESDPSLGHEPEEEDEEEEEEEEELLLENESRPESSF

SMDSELSRNRENGGGGVPGVPGAGGGAAKALADEKALVLGKVMENVGLGALP

QYGELLADKQKRGAFLKRAAGGGDAGDDDDAGGCGDAGAGGAVNGRGGGFA

PGTEPFPGLFPRKPAPLPSPGLNSAAKRIKVEKDLELPPAALIPSENVYSQWLVGYA

ASRHFMKDPFLGFTDARQSPFATSSEHSSENGSLRFSTPPGDLLDGGLSGRSGTAS

GGSTPHLGGPGPGRPSSKEGRRSDTCEYCGKVFKNCSNLTVHRRSHTGERPYKCE

LCNYACAQSSKLTRHMKTHGQIGKEVYRCDICQMPFSVYSTLEKHMKKWHGEHL

LTNDVKIEQAERS

GIMAP5 MGGFQRGKYGTMAEGRSEDNLSATPPALRIILVGKTGCGKSATGNSILGQPVFES

SEQID

(GTPase, IMAP KLRAQSVTRTCQVKTGTWNGRKVLVVDTPSIFESQADTQELYKNIGDCYLLSAPG

NO. family member PHVLLLVIQLGRFTAQDTVAIRKVKEVFGTGAMRHVVILFTHKEDLGGQALDDYV

56 5) ANTDNCSLKDLVRECERRYCAFNNWGSVEEQRQQQAELLAVIERLGREREGSFH

>sp|Q96F15|GI SNDLFLDAQLLQRTGAGACQEDYRQYQAKVEWQVEKHKQELRENESNWAYKAL MA5_HUMAN LRVKHLMLLHYEIFVFLLLCSILFFIIFLFIFHYI

GTPase IMAP

family member

5

PTPRC (Protein MYLWLKLLAFGFAFLDTEVFVTGQSPTPSPTGLTTAKMPSVPLSSDPLPTHTTAFS

SEQID

tyrosine PASTFERENDFSETTTSLSPDNTSTQVSPDSLDNASAFNTTGVSSVQTPHLPTHAD

NO. phosphatase, SQTPSAGTDTQTFSGSAANAKLNPTPGSNAISDVPGERSTASTFPTDPVSPLTTTL

57 receptor type, SLAHHSSAALPARTSNTTITANTSDAYLNASETTTLSPSGSAVISTTTIATTPSKPTCD C) EKYANITVDYLYNKETKLFTAKLNVNENVECGNNTCTNNEVHNLTECKNASVSISH

>sp|P08575|PT NSCTAPDKTLILDVPPGVEKFQLHDCTQVEKADTTICLKWKNIETFTCDTQNITYRF PRC_HUMAN QCGNMIFDNKEIKLENLEPEHEYKCDSEILYNNHKFTNASKIIKTDFGSPGEPQIIFC Receptor-type RSEAAHQGVITWNPPQRSFHNFTLCYIKETEKDCLNLDKNLIKYDLQNLKPYTKYV tyrosine-protein LSLHAYIIAKVQRNGSAAMCHFTTKSAPPSQVWNMTVSMTSDNSMHVKCRPPR phosphatase C DRNGPHERYHLEVEAGNTLVRNESHKNCDFRVKDLQYSTDYTFKAYFHNGDYPG

EPFILHHSTSYNSKALIAFLAFLIIVTSIALLVVLYKIYDLHKKRSCNLDEQQELVERDD

EKQLMNVEPIHADILLETYKRKIADEGRLFLAEFQSIPRVFSKFPIKEARKPFNQNKN

RYVDILPYDYNRVELSEINGDAGSNYINASYIDGFKEPRKYIAAQGPRDETVDDFW

RMIWEQKATVIVMVTRCEEGNRNKCAEYWPSMEEGTRAFGDVVVKINQHKRC

PDYIIQKLNIVNKKEKATGREVTHIQFTSWPDHGVPEDPHLLLKLRRRVNAFSNFF

SGPIVVHCSAGVGRTGTYIGIDAMLEGLEAENKVDVYGYVVKLRRQRCLMVQVE

AQYILIHQALVEYNQFGETEVNLSELHPYLHNMKKRDPPSEPSPLEAEFQRLPSYRS

WRTQHIGNQEENKSKNRNSNVIPYDYNRVPLKHELEMSKESEHDSDESSDDDSD

SEEPSKYINASFIMSYWKPEVMIAAQGPLKETIGDFWQMIFQRKVKVIVMLTELK

HGDQEICAQYWGEGKQTYGDIEVDLKDTDKSSTYTLRVFELRHSKRKDSRTVYQY

QYTNWSVEQLPAEPKELISMIQVVKQKLPQKNSSEGNKHHKSTPLLIHCRDGSQQ

TGIFCALLNLLESAETEEVVDIFQVVKALRKARPGMVSTFEQYQFLYDVIASTYPAQ

NGQVKKNNHQEDKIEFDNEVDKVKQDANCVNPLGAPEKLPEAKEQAEGSEPTS

GTEGPEHSVNGPASPALNQGS

EXOSC1 MAPPVRYCIPGERLCNLEEGSPGSGTYTRHGYIFSSLAGCLMKSSENGALPVVSVV

SEQID

(Exosome RETESQLLPDVGAIVTCKVSSINSRFAKVHILYVGSMPLKNSFRGTIRKEDVRATEK Component 1) DKVEIYKSFRPGDIVLAKVISLGDAQSNYLLTTAEN ELGVVVAHSESGIQMVPISW

NO.

>sp | Q9Y3B2 | EX CEMQCPKTHTKEFRKVARVQPEFLQT

58 OSl_H UMAN

Exosome

complex

component

CSL4

EXOSC9 MKETPLSNCERRFLLRAIEEKKRLDGRQTYDYRNI RISFGTDYGCCIVELGKTRVLG

SEQ I D

(Exosome QVSCELVSPKLN RATEGILFFN LELSQMAAPAFEPGRQSDLLVKLN RLMERCLRNS

NO. component 9) KCI DTESLCVVAGEKVWQI RVDLH LLN H DGNI IDAASIAAIVALCH FRRPDVSVQG

59 >sp 1 Q062651 EX DEVTLYTPEERDPVPLSIH HM PICVSFAFFQQGTYLLVDPN EREERVMDGLLVIAM

OS9_H UMAN N KH REICTIQSSGGIM LLKDQVLRCSKIAGVKVAEITELILKALENDQKVRKEGGKF

Exosome GFAESIANQRITAFKMEKAPI DTSDVEEKAEEI IAEAEPPSEVVSTPVLWTPGTAQI complex GEGVENSWGDLEDSEKEDDEGGGDQAII LDGI KM DTGVEVSDIGSQDAPI ILSDS component EEEEMI ILEPDKN PKKIRTQTTSAKQEKAPSKKPVKRRKKKRAAN

P45

EXAMPLES

[195] EXAMPLE 1 : Materials and methods

[196] Isolation and cultivation of human Treg/Teff cells

[197] Stable human alloantigen-specific Tregs and Teffs derived from sorted CD4+CD25high and CD4+CD25- peripheral blood T cells were established as our recent work (Probst-Kepper et al, 2009; He et al, 2012, Molecular Systems Biology). IMDM (Gibco) supplemented with 10% FCS (Gibco), 100 U/ml penicillin, 100 ug/ml streptomycin (PAA) and 50 μΜ beta-mercaptoethanol (Sigma-Aldrich) was used for cell culture. Recombinant human IL2 (Proleukin, Novartis) was added daily to Treg culture medium at a concentration of 100 U/ml, as we previously described (Probst- Kepper et al, 2009) and in a similar way by others (Stockis et al, 2009; Tran et al, 2009). All the Tregs/Teffs were stably maintained and restimulated by allogeneic Epstein-Barr virus (EBV)-transformed B cells (EBV-B cells) weekly as previously described (Probst-Kepper et al, 2009). Informed consent was obtained before the blood was taken. In this work, BD Arialll was used for sorting.

[198] Flow-cytometry analysis and ROS measurement

[199] Human FOXP3 expression was detected with anti-FOXP3 mAbs after fixation and permeabilization of cells by the protocol provided by the manufacturer (206D, Biolegend). DJ-1 protein expression was analyzed by intracellular staining with mAbs against human DJ-1/PARK7 (ab18257, Abeam) followed by a secondary antibody Alexa Fluor® 647 goat anti-rabbit IgG (H+L) (highly cross-adsorbed) (Invitrogen). ROS Mitochondria MitoSOX™ Red (5uM) were used to detect ROS burst in Tregs by FACS measurement. BD Fortessa was used for data acquisition, and the data were analyzed with FlowJo software.

[200] Suppression assay

[201] Following the transfection of human Tregs with various siRNAs (against human DJ-1/PARK7 and/or FOXP3 (or non-silencing control siRNA) for 1 day, Tregs were co-cultured with CFSE-labelled Teffs (1 E5) with different ratios, as well as irradiated EBV-B cells (1 E5, without IL2 addition). CFSE (from Invitrogen) at a concentration of 1 μΜ was used to label Teffs. The human cells were cultured for 4 or 5 days in 96-well flat bottom plates and the gated DAPI (from Invitrogen) negative and CD4+, CFSE stained Teffs were measured by BD Fortessa.

[202] Phosphorylation assessment by FACS

[203] Following the transfection of human Tregs with specific siRNA against human DJ-1 or non-specific siRNA for 1 day, Tregs were stimulated by anti-CD3/-CD28/IL2 for different lengths of time. The monoclonal antibodies recognizing the specific phosphorylation sites for Alex647 STAT1 [pY701], PE STAT3[pY705], Alex647 STAT5[pY694], PE-Cy7 ERK1/2[pT202/pY204], and Alex647 AKT[pS473] were all BD Phosflow products. Rabbit mAB JNK1/2[pT183/pY185] and its secondary antibody Alex647 goat anti-rabbit IgG were from Invitrogen. The staining and measurement of the phosphorylation of these proteins was performed using BD Phosflow protocols.

[204] siRNA knockdown

[205] Specific siRNA against human DJ-1/PARK7 and/or FOXP3 (or non-silencing control siRNA) were obtained from Qiagen or Santa Cruz Biotechnology, respectively. Specific siRNA against human PARK7 or FOXP3 targets the sequence AAT GGA GGT CAT TAC ACC TAC (SEQ ID NO: 1 ) or CAG CTG GAG GGC TGC ACC CAA (SEQ ID NO: 2), respectively. One hundred picomoles of siRNA was mixed with Tregs resuspended in 100 μΙ human T cell Nucleofector solution (Lonza Amaxa). The mixture was immediately exposed to electroporation by the 4D- Nucleofector device (Lonza Amaxa) and placed in 37C pre-warmed IMDM. The cytokinel OO U/ml IL2 was added 4 hour later after electroporation. Before a further stimulation experiment, the Tregs were rested for 1 day.

[206] Co-IP and Western Blotting

[207] We used the lysis buffer containing 0.2% Triton X-100, 2mM EDTA with 100mM NaCI to lyse unstimulated or stimulated Tregs or Teffs. Stimulation was done by anti-CD3/-CD28 beads for 5 hours with or without IL2 addition. The proteins (3 g/ l) were incubated with antibody (10 g/1000 g protein) against DJ-1 (ab18257, Abeam) or normal rabbit control IgG (sc-2027, Santa Cruz) for 5 hours followed by the addition of dynabeads protein G (100.03D, Invitrogen, 1200ug/1 OOOug protein) overnight. Protein complex bound by DJ-1 or IgG were then eluted (RapiGest SF, Waters) and washed for the follow-up mass spectrum proteomic analysis. For the Western blotting analysis, samples were stained with the primary antibodies against DJ-1 (ab18257, Abeam) or control GAPDH (sc-25778, Santa Cruz) followed by the secondary antibody goat anti-rabbit IgG-HRP (172-1019, Bio-Rad).

[208] Real-time RT-PCR (qPCR)

[209] RNA was isolated with the RNeasy Mini Kit (Qiagen) according to manufacturer's protocol and additionally purified by on-column RNase-free DNase digestion (Qiagen). Purified and concentrated RNA was then reverse-transcribed using Superscript III reverse transcriptase (Invitrogen). qPCR was conducted on a LightCycler 480 (Roche) as previously described (Pfoertner et al, 2006). The following primers were finally used in our qPCR analysis. Human PARK7/DJ-1 forward (5-3) TTG TAG GCT GAG AAA TCT CTG TG (SEQ ID NO: 3); PARK7 reverse (5-3) ATC CAT TCT CAC TGT GTT CGC (SEQ ID NO: 4); FOXP3 forward ACC TAC GCC ACG CTC ATC (SEQ ID NO: 5); FOXP3 reverse TCATTG AGTGTC CGC TGC T (SEQ ID NO: 6); CTLA4 forward TGC AGC AGT TAG TTC GGG GTT GTT (SEQ ID NO: 7); CTLA4 reverse CTG GCT CTG TTG GGG GCATTT TC (SEQ ID NO: 8); TGFB1 forward CGC AAG GAC CTC GGC TGG AAG TGG (SEQ ID NO: 9); TGFB1 reverse GAG GCG CCC GGG TTA TGC TGG TTG (SEQ ID NO: 10). The primers GARP forward GAT GGG GAA ACT GAG GCT TAG GAA (SEQ ID NO: 1 1 ); GARP reverse ACC CCC AAT CTC ACC CCA CAA ATA (SEQ ID NO: 12); LGMN forward CTC GCT CCA GGA CCT TCT TCA CAA (SEQ ID NO: 13); LGMN reverse GCT TCC TGC TCC TCA AAA CTA ACA (SEQ ID NO: 14) and IL4 forward CGG CAA CTT TGT CCA CGG A (SEQ ID NO: 15), IL4 reverse TCT GTT ACG GTC AAC TCG GTG (SEQ ID NO: 16) were also from our previous work (Probst-Kepper et al, 2009). We also used qPCR primers from Qiagen for the genes RPS9, GAPDH, PLAU, IL1 R1 , S1 PR1 , IKZF4 (EOS), IKZF2 (Helios), GITR, LGALS3, CD127, IL13, CSF2, IL5, and IL2. RPS9 or GAPDH was used as an internal standard (Bruder et al, 2004) in our qPCR analysis.

[210] Microarray measurement and data preprocessing [211] The cells were centrifuged, and the cell pellets were lysed in RLT buffer (Qiagen) and immediately stored at -70C. RNA was isolated with the RNeasy Mini Kit (Qiagen) according to manufacturer's protocol and additionally purified by on-column RNase-free DNase digestion (Qiagen). RNA quality was checked by RNA 6000 Nano assay (2100 Bioanalyzer, Agilent). For oligonucleotide microarray hybridization, RNA was labeled, fragmented, and hybridized to an Affymetrix GeneChip Human Gene 2.0 ST oligonucleotide array at the Genomics Core facility of the EMBL (Heidelberg). After the arrays were scanned, the expression value for each gene was calculated by using Affymetrix Microarray software 5.0 (MAS5). The average intensity difference values were normalized across the sample set. Probe sets that were absent in all samples, according to Affymetrix flags, were removed.

[212] Correlation network construction and analysis Network construction

[213] In this work, we demonstrated the identification of key genes by constructing and analyzing a Treg-specific correlation network. The correlation network construction and analysis has been described in detail in our recent work (He et al., 2012, Molecular Systems Biology). We constructed the correlation network by identifying correlation linkages among pairs of genes. The correlation linkages were identified by employing both the LC and the TC methods. Both methods are capable of discovering potential functional association between genes from time-series data by considering positive/inverted correlation and time shift. A significant correlation with time shift between two genes might indicate a transcription regulatory relationship (Bar-Joseph et al, 2012). But to obtain accurate inference, we need much additional information, a big portion of which are not available. We therefore only simply considered the pairs with this type of correlation as potential function- associated linkages in this work by not distinguishing the specific type of detailed functional association (e.g., signal transduction, transcription regulation or in the same pathways). The LC method has been widely used to identify potential functional association mainly based on a point-to-point comparison of gene expression values from time-series data as recently reviewed (Bar-Joseph et al, 2012). The TC method has also been demonstrated to be useful in identifying potential functional association from time-series data and to be complementary to the LC method based on extracting main features of the change trend and the change level of gene expression between consecutive time points (He and Zeng, 2006). Due to different principles behind the LC and the TC methods, we therefore combined both methods to complement each other in order to identify more complete potential functional associations between genes. For this purpose, we calculated the LC score as defined by the LC method (Qian et al, 2001 ), the maximal matched change trend (sc) score and the correlation coefficient (cc) score for the maximal matched change trend as defined by the TC method (He and Zeng, 2006) for each pair of genes in all the time- series data sets of Tregs and Teffs. We then calculated PLC for the scores resulting from the LC method as described (Qian et al, 2001 ). We also calculated PTC1 for the TC method by extraction procedure I, as previously described (He and Zeng, 2006). For the TC method, we here introduced another adapted P-value (PTC2) calculation based on the reordered sc and cc distribution curve. Briefly speaking, the reason to reorder the distribution table (curve) is that we found that some of the pairs, which have a very high cc score but the sc score is not very high, might still have a high chance to be potentially functionally linked. So far, we obtained three different P- values (PTC1 , PTC2, and PLC) for each pair of genes in each replicate of the time- series data set generated for a given cell type (Tregs or Teffs). In the following, we set rules to extract Treg-specific correlation linkages. First, to guarantee the reproducibility of the results, we restricted the significantly correlated pairs to those repeatedly showing significant P-values in both replicates of Tregs constantly by one of the three P-values (PTC1 , PTC2, and PLC). A standard P-value cutoff of 0.05, the well established and extensively used threshold was applied. Second, in order to obtain cumulative evidence generated in both replicates and gained by both methods, we employed naive Bayesian integration (combination) (Chen et al, 2005) by multiplying different P-values from both replicates by the LC and the TC methods. This is based on the assumption of the independency of the P-values generated by two different methods due to the utilization of different principles and the independency of the results from each replicate due to the difficulty in obtaining synchronized T-cell stage before activation although all the T cells were at the resting stage. Since both PTC1 and PTC2 were caused by the TC method, we chose the minimal P-value generated by one of them. Thus, only four P-values were eventually utilized for the integration purpose. The cutoff for the integrated P-values was chosen at 1 e_9 based on a more stringent but also well-established P-value threshold 0.01 . The overall threshold 1 e_9 was even stricter than the product of the four individual P- values ((0.01 )4.1 e_8) in order to avoid the cases, such as those pairs with all the individual P-values very close to the threshold of 0.01 , which could be marginal. We therefore set min (PTC1 ,Treg1 ^*PTC1 ,Treg2, PTC2,Treg1 ^* PTC2,Treg2) ^*PLC,Treg1 ^*PLC,Treg2p1 e_9, where min () indicates the minimal value of the two products of P values; Treg1/2 indicates the replicate of Treg 1 or 2. In the end, we only included the pairs satisfying both of the two criteria for the reproducibility and the integrated evidence in Tregs but the same pairs did not even meet the standards of the reproducibility in Teffs, as Treg-specific correlation linkages. The strict criteria of the reproducibility largely excluded those pairs with integrated P-values slightly higher than the integrated P-value threshold in Tregs but slightly lower than the integrated threshold in Teffs. Obviously, the pairs that cannot satisfy the basic prerequisites of the reproducibility (p0.05) has very less chance to pass the integrated P-value threshold (based on 0.01 ). For example, it has been found that where 99 and 95.5% of all the Treg-specific correlation linkages show around 3- and 10-fold less P-values, respectively, in average for each of the four individual P-values in Tregs than in Teffs. For the remaining tiny proportion (1 %) of the correlation linkages, they showed a very significant correlation only in one of the two replicates of Teffs but had no significance in another one, which still causes a very small final product of P-values integrated from replicates. Apparently, we cannot consider this tiny fraction as significantly correlated pairs in Teffs without consistent results between replicates. Thus, all of linkages including the tiny fraction were Treg-specific correlation interactions with high confidence.

[214] EXAMPLE 2: DJ-1 is highly expressed in Tregs and Treg-important genes are enriched in DJ-1 correlation network

[215] Starting from our own published datasets, we were able to find that DJ-1 was highly expressed in both unstimulated and stimulated human Tregs and Teffs according to the high-time-resolution time-series transcriptome data in the first 6 hrs following TCR stimulation [19]. Quantitative Realtime PCR results from other healthy donors have also confirmed that its expression level is as high as some highly- expressed reference genes such as RPS9 (Figure 1 ). As expected, DJ-1 protein is also highly expressed in both human Tregs and Teffs (Figure 1 , western blot and FACS figure).

[216] Furthermore, by utilizing a network strategy which has a potential to infer novel key genes for Tregs from Treg-specific correlation network [19], we analysed the first- degree neighbourhoods in the DJ-1 subnetwork. We cannot find a significant enrichment for the collection of 400 T-cell function related genes. However, we noticed that almost all of its first-degree neighbours were significantly enriched for the collection of the 400 genes. Since the second-degree neighbours in the subnetwork might also influence the activity or function of the given gene/node [20], we further analysed the subnetwork composed of second-order neighbours of DJ-1. Intriguingly, we found that in the second-degree gene network DJ-1 was highly connected with well-known key players for Treg function (4.3E-12), such as FOXP3, CTLA4, ICOS, GATA3, CD44 and others [13, 21 ]. This indicates that DJ-1 is probably involved in Treg suppressor function (Figure 2) according to our network analysis strategy.

[217] EXAMPLE 3: Inhibiting DJ-1 promotes Treg suppressor function

In order to test whether DJ-1 plays a role in the suppressor function of Tregs, we knocked-down DJ-1 in human natural Tregs (nTregs) with DJ-1 specific siRNA (si- DJ-1). After co-culturing nTregs with carboxyfluorescein succinimidyl ester (CFSE)- labelled Teffs at various ratios, Epstein-Barr virus (EBV)-transformed B cells (representing antigen presenting cells), unexpectedly, we observed that knockdown of DJ-1 significantly enhanced the Treg suppressor function in the cases of higher (eg. 1 :4 and 1 :8) but not lower ratios (Figure 3).

[218] Since the control Tregs (with non-specific siRNA, si_NS) have already quite high suppressive function at lower ratios, we expect that it is almost impossible to further increase their suppressor function. For this reason, we proposed to improve the suppressive function for the so-called 'defective' nTregs, i.e, with impaired suppressor function, which is often the case in autoimmune diseases. As FOXP3 is the so-called master regulator of Tregs and its deficiency impairs Treg suppressor function, we here tested the effects of DJ-1 on nTregs with FOXP3 deficiency. As expected, knocking-down FOXP3 indeed led to an impairment of human Treg suppressor function (Figure 3). Remarkably, silencing of DJ-1 rescued the impaired Treg suppressive function (Figure 3). Recently, D/^'-7-knockout mice have shown reduced inflammation in white adipose tissue (Kim et al. 2014) although one has no clue whether Treg function has been enhanced or not. Here, we further asked whether Dj-1 -knockout murine CD4+CD25+Tregs demonstrated enhanced suppressive function by co-culturing sorted Dj-1^'1', Dj-1^'l+ or Dj-1^+I+ Tregs with CFSE- labelled WT Ths and feeder cells.

[219] EXAMPLE 4: DJ-1 mediates Treg suppressor function via FOXP3 and CTLA4

[220] To figure out the mechanism underlying DJ-7-medidated Treg suppressor function, we further assessed the effects of DJ-1 on the expression of known Treg key genes. Remarkably, knocking-down DJ-1 followed by anti-CD3/-CD28/IL2 stimulation significantly up-regulated several reported Treg important genes in FOXP3-deficient human Tregs, such as FOXP3, GARP, EOS (IKZF4) and others (Figure 4). The regulation of some gene expression was FOXP3-dependent but the expression of others was not (Figure 4). Concordantly, knockdown of DJ-1 increased FOXP3 protein expression in FOXP3-silenced Tregs (Figure 4). As FOXP3 normally inhibits the expression of cytokines, knocking-down FOXP3 indeed increased their expression (Figure 4, right). Interestingly, silencing of DJ-1 significantly inhibited the expression of these increased cytokines in FOXP3-silenced Tregs possibly by rescuing FOXP3 expression (Figure 4, right).

[221] Reactive oxygen species (ROS) are regulated by DJ-1 in other cellular types and conditions (Jeong et al. (2012); Waak et al. (2009)) and play an important role in signaling transduction (Lee et al. (201 1 ); Kahle et al. (2009); Niedbala et al. (2007); Brahmachari et al. (2010)). For this reason, we further investigated whether ROS were involved in DJ-7-mediated nTreg suppressor function. More recently, ROS were demonstrated to be involved in antigen-specific T cell activation when the authors used total CD4+ or CD8+ T cells as subjects Sena et al. (2013)). Our results show that the ROS burst level was significantly increased in DJ-7-knockdown nTregs (Figure 5).

[222] Notably, inhibiting the ROS burst with a specific ROS inhibitor (Diphenyleneiodonium, DPI) significantly decreased the expression of some Treg key genes (FOXP3 and CTLA4) in a dose-dependent manner, which were upregulated after silencing DJ-1 in FOXP3-deficiency Tregs (Figure 5, right).

[223] Moreover, ROS inhibitor did not result in significant cell death of Tregs. However, we were unable to observe any significant effect on several tested potential Treg-relevant signalling pathways, such as STAT5, ERK, AKT and others following DJ-1 knockdown in FOXP3-deficient Tregs. These lines of evidence support our hypothesis that DJ-1 might play an unexpected inhibitory role in Treg suppressor function in contrast to its classical 'positive' role in neurons and tumor cells.

[224] EXAMPLE 5: DJ-1 mediates Treg suppressor function via regulating cell cycle and TCR signaling pathway.

[225] To systematically investigate which genes and pathways/subnetworks were involved in DJ-7-mediated Treg suppressor function, we measured genome-scale transcription of si_NS treated nTregs, FOXP3-knockdown Tregs, FOXP3 and DJ-1- dual-knockdown Tregs. Since stimulation is required for Treg suppressor function, before transcriptome measurement we first knocked-down FOXP3 and/or DJ-1 by specific siRNA and then stimulated Tregs for 1 day. Overall, in two independent microarray sets from different human donors, we repeatedly observed that most of genes were downregulated (494) while only a very small fraction of genes (62) were upregulated following DJ-1 inhibition (Figure 6).

[226] This mainstream downregulation is very much consistent with the essential known function of DJ-1 as a coactivator [3]. As a snapshot, the genes (277) upregulated by FOXP3 knockdown but then downregulated by DJ-1 knockdown, referred to as FOXP3-dependent downregulated genes, were mainly enriched for the processes of nucleotide binding (P-value=8.5E-1 1 ), ribonucleotide binding (2.6E-8), microtubule organizing center (2.9E-6), cell cycle (1 .3E-6), small GTPase regulator activity (8.2E-3) and ubiquitin-mediated proteolysis (9.6E-3). Among these processes, DJ-1 is known to bind to RNA even at a very low concentration [4]. Since DJ-1 interacts with a number of E3 ligases(Xiong et al. (2009); Parsanejad et al. (2014)), it is not shocking to observe its downstream regulatory effects on the gene expression involved in ubiquitin-mediated proteolysis. Furthermore, a recent quantitative interaction proteomics analysis shows that proteins binding to several neurodegenerative disease proteins are significantly enriched for the genes related to proteolysis (Hosp et al. (2015)). The common theme on ubiquitin-mediated proteolysis of DJ-1 action observed by us and others although using different techniques, definitely signifies the proteolysis function of DJ-1. Surprisingly, the TCR signaling pathway (1 .5E-2) that was regulated by FOXP3 (Marson et al. (2007)) was also significantly affected by DJ-1 (Figure 6), again indicating the important role of DJ-1 in Treg suppressor function. Out of the 217 FOXP3-independent gene downregulated by DJ-1 expression reduction, we could observe that the processes of ribonucleotide binding, GTPase regulator activity and cell cycle were still significantly enriched. This in fact validates the aforementioned pathway results of FOXP3- dependent downregulated genes although the affected genes of the same pathways are different. A positive transcription effect of DJ-1 on genes forming endoplasmic reticulum membrane was also observed among FOXP3-independent downregulated genes.

[227] For the 29 downregulated genes by FOXP3 but upregulated by DJ-1 downregulation, we could not find a significant enrichment for any known biological process or pathway, again exhibiting the non-essentiality of the down-regulatory activity of DJ-1. DJ-1 knockdown enhances only 33 FOXP3-independent genes. Inhibiting DJ-1 not only significantly downregulated E1 ubiquitin-activating enzyme (UBE1 ) and E2 ubiquitin-conjugating enzymes UBE2D3 and UBE2O, but also enhances some of E3 ubiquitin ligases (e.g., UBE4B, TRIP12 and SMURF2), which might compensate each other to modulate ubiquitin-mediated proteolysis.

[228] More specifically, decrease of SKP2 (S-phase kinase-associated protein 2) was observed in DJ-7-FOXP3-siRNA Tregs relative to FOXP3-siRNA Tregs. Interestingly, knockdown of SKP2 converts diabetogenic T cells to FOXP3+ regulatory T cells [31 ]. In addition to SKP2, several other genes regulating S-phase arrest from the IPA database were also downregulated in DJ-1 and FOXP3 dual knockdown Tregs compared with FOXP3-siRNA Tregs. The downregulation of those genes together following DJ-1 knockdown might inhibit Treg proliferation, reminiscent characteristics of Tregs. Although in the peripheral immunocytes, we observed that many genes which inhibits congenital malformation of brain were downregulated following DJ-1 knockdown, again demonstrating that DJ-1 does not only play a privilege role in neurons. To further understand the hierarchal structure through which DJ-1 mediates Treg suppressor function, we further mapped the down- or up- regulated genes in DJ-7-FOXP3-siRNA vs FOXP3-siRNA Tregs into known transcription regulatory networks. The Ingenuity Pathway Analysis (IPA) of the transcriptomics data shows that DJ-1 controlled the down-regulated genes via NUPR1 , PIAS1 , TCR and EP400 in Tregs (Figure 7). It is worthy to notice that EP400 modulates cell fate decisions by the regulation of ROS homeostasis (Mattera et al. (2010)) and DJ-1 directly binds to the androgen receptor-binding region of PIAS1 (protein inhibitor of activated STAT)(Takahashi et al. (2001 )).

[229] EXAMPLE 6: DJ-1 binds to GZMB, RNA processing factors and MAPK signaling proteins preferentially in stimulated Tregs but LGALS3BP in unstimulated Tregs.

[230] Since DJ-1 was highly expressed in both unstimulated and stimulated Tregs, next, we examined whether and how DJ-1 mediated Treg suppressor function via preferentially binding to certain binding partners in different statuses of Tregs by co- immuno-precipitation (IP) proteomic analysis. Following the Co-IP mass spectrum analysis with strict criteria (see Methods), we compared the abundancy of DJ-1 binding partners between unstimulated and stimulated Tregs/Teffs. First of all, our results were able to confirm the 12 known partners (Figure 8) of DJ-1 measured in other cellular types, including DAXX and others, showing the reliability of our techniques.

[231] In order to obtain more robust results, we determined those binding partners which showed similar change trends between unstimulated and stimulated Tregs, Teffs as well as Tregs treated without the addition of IL2. Very interestingly, six proteins regulating RNA splicing preferentially bound in the stimulated rather than resting Tregs/Teffs (Figure 8). Furthermore, UPF1 (the regulator of nonsense- mediated mRNA decay) also mainly bound in stimulated Tregs/Teff. Another RNA processing protein, a pre-mRNA cleavage and polyadenylation specificity factor (PPP1 CB) also mainly bound in stimulated Tregs. These Co-IP proteomic results are in concordance with our observation on the RNA processing pathways that were significantly affected in transcription levels by DJ-1 expression. A protein ATP5D (a subunit of mitochondrial ATP synthase) mainly sticked to DJ-1 in stimulated Tregs/Teffs, reminding the essential role of DJ-1 in mitochondrial function. Interestingly, two translation initiation factors (EIF2A and EIF5B) also preferentially bound to DJ-1 in stimulated Tregs/Teffs. Satisfyingly, we also found that some proteins preferentially-bound in stimulated Tregs, such as MAP4K1 and ANXA4, which regulate JNK-STAT, MAPK and NFKB signalling pathways, indicating a potent role of DJ-1 in Treg suppressor function since these pathways provide clear clues linking DJ-1 and downstream T cell functions/cellular phenotypes.

[232] Unexpectedly, Granzyme B (GZMB), a known important Treg gene [34], preferentially bound to both stimulated Tregs and Teffs. But this preference was much higher in Tregs than in Teffs (>8 vs ~2, Figure 8), indicating a specific role of GZMB in DJ-7-mediated Treg suppressor function. In contrast, we noticed that Galetin-3-binding protein (LGALS3BP) bound with DJ-1 preferentially in unstimulated Tregs than in stimulated Tregs with a factor of up to 10 for both Treg sample pairs. Since Galectin 3 regulates Treg function(Fermino et al. (2013)), this observation was already able to partially illustrate how DJ-1 mediated Treg suppressor function in this work.

[233] Furthermore, we determined 8 proteins, which bound to DJ-1 preferentially in unstimulated Tregs/Teffs. It is worthy to mention that a RNA binding factor MOV10 (RISC complex RNA helicase) bound with DJ-1 at least 10 folds higher in unstimulated Tregs/Teffs than in the stimulated ones, again showing that RNA processing pathways were one of the main binding sources of DJ-1. DJ-1 regulates cellular metabolic homeostasis via modulating ROS levels as demonstrated in murine skeletal muscles(Shi et al. (2015)). Interestingly, in human Tregs/Teffs, we also observed that PDHB (pyruvate dehydrogenase (lipoamide) beta), the essential component of glucose catabolism, preferentially bound in unstimulated Tregs/Teffs, not only confirming the reports about the role of DJ-1 in metabolic homeostasis, but also discovering a molecular pathway underlying the metabolic function.

[234] Discussion

This is the first work to demonstrate that a well-known Parkinson's disease gene DJ- 1 unexpectedly mediates the suppressive function of a peripheral immunocyte, ie. Tregs, provoking reconsideration that disease genes in multiple cellular types instead of single cellular types might contribute to the pathogenesis of a complex neurodegenerative disease. We are the first to show that inhibiting a gene (DJ-1 ) can significantly rescue FOXP3-deficient Treg suppressor function, which will provide a promising alternative strategy for targeting autoimmune diseases since inhibition of a target, e.g., by a promising siRNA in vivo treatment (Rettig et al. (2012)), is generally easier than activation from a drug-development point of view.

[235] It must be noted that as used herein, the singular forms "a", "an", and "the", include plural references unless the context clearly indicates otherwise. Thus, for example, reference to "a reagent" includes one or more of such different reagents and reference to "the method" includes reference to equivalent steps and methods known to those of ordinary skill in the art that could be modified or substituted for the methods described herein.

[236] All publications and patents cited in this disclosure are incorporated by reference in their entirety. To the extent the material incorporated by reference contradicts or is inconsistent with this specification, the specification will supersede any such material.

[237] Unless otherwise indicated, the term "at least" preceding a series of elements is to be understood to refer to every element in the series. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the present invention.

[238] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step. When used herein the term "comprising" can be substituted with the term "containing" or sometimes when used herein with the term "having".

[239] When used herein "consisting of excludes any element, step, or ingredient not specified in the claim element. When used herein, "consisting essentially of does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim.

[240] In each instance herein any of the terms "comprising", "consisting essentially of and "consisting of may be replaced with either of the other two terms.

[241] Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[242] When used herein, the term "about" is understood to mean that there can be variation in the respective value or range (such as pH, concentration, percentage, molarity, number of amino acids, time etc.) that can be up to 5%, up to 10%, up to 15% or up to and including 20% of the given value. For example, if a formulation comprises about 5 mg/ml of a compound, this is understood to mean that a formulation can have between 4 and 6 mg/ml, preferably between 4.25 and 5.75 mg/ml, more preferably between 4.5 and 5.5 mg/ml and even more preferably between 4.75 and 5.25 mg/ml, with the most preferred being 5 mg/ml. As used herein, an interval which is defined as "(from) X to Y" equates with an interval which is defined as "between X and Y". Both intervals specifically include the upper limit and also the lower limit. This means that for example an interval of "5 mg/ml to 10 mg/ml" or "between 5 mg/ml and 10 mg/ml" includes a concentration of 5, 6, 7, 8, 9, and 10 mg/ml as well as any given intermediate value. REFERENCES Arya M, Shergill I S, Williamson M, Gommersall L, Arya N, Patel HRH "Basic principles of quantitative real time PCR" Expert Rev. Mol. Diagn. 5(2):209- 2192. Abou-Sleiman P.M., Healy D.G., Quinn N., Lees A.J. , and Wood N.W., The role of pathogenic DJ-1 mutations in Parkinson's disease. Ann Neurol, 2003. 54(3): p. 283-6.

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Claims

Inhibitor of DJ-1 (PARK7) for use in the treatment or prevention of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer.

Inhibitor for the use of claim 1 , wherein the inhibitor is a nucleic acid molecule, preferably a siRNA or a miRNA, a binding protein, a small molecule or a compound.

Inhibitor for the use of claim 2, wherein the binding protein is selected from the group consisting of an antibody or a proteinaceous binding molecule with antibody-like binding properties.

Inhibitor for use of claim 2, wherein the nucleic acid molecule, preferably a siRNA, has a sequence identity of at least 50 %, 60%, 70%, 80%, 90%, 95%, 98%, 99% or 100% to SEQ ID NO: 1 .

Inhibitor for use of claim 2, wherein the nucleic acid molecule, preferably a siRNA or a miRNA, are provided within a plasmid vector and/or are modified or encapsulated by synthetic or natural nanoparticles.

Inhibitor for use of claim 5, wherein the nanoparticle is a liposomal nanoparticle.

Inhibitor for the use of any one of claims 1 -6, wherein the inhibitor increases regulatory T cell (Treg) suppressor function of a Treg compared to the Treg before it has been contacted with the inhibitor.

Inhibitorfor use of claim 7, wherein the Treg is a human natural Treg (nTreg) and/or a Treg with impaired suppressor function.

9. Inhibitor for use of claim 8, wherein the Treg with an impaired suppressor function is a Treg that has been obtained from a subject having an autoimmune disease, an allergy, an infectious disease or a cancer.

10. Pharmaceutical composition comprising the inhibitor as defined in any one of claims 1 -9.

1 1 . Method for screening for an inhibitor or activator of DJ-1 , the method comprising

(b) measuring suppressor function of Tregs, wherein a increase in suppressor function of said Tregs compared to said Tregs before contacting indicates that the nucleic acid molecule, preferably a siRNA or a miRNA, the binding protein, the small molecule or the compound of interest serves as an inhibitor of DJ-1 , or wherein an decrease in the suppressor function of said Tregs compared to said Tregs before contacting indicates that the nucleic acid molecule, preferably a siRNA or a miRNA, the binding protein, the small molecule or the compound of the interest serves as an activator of DJ-1 .

12. Method for determining whether or not a cell is susceptible to the treatment with an inhibitor as defined in any one of claims 1 -9, comprising determining whether or not said cell expresses DJ-1 .

13. Kit comprising an inhibitor of DJ-1 as defined in any one of claims 1 -9.

14. Inhibitor of DJ-1 (PARK7) for use in treating or preventing of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer, wherein the treating or preventing comprises

(i) contacting Tregs and/or (T effector cells) Teffs with the inhibitor.

15. Inhibitor of DJ-1 (PARK7) for use in treating or preventing of one or more of autoimmune disease, allergy, infectious disease or cancer, wherein the cancer is not lung cancer, wherein the treating or preventing comprises

(i) obtaining Tregs and/or Teffs from a subject;

(ii) contacting said Tregs and/or Teffs with the inhibitor, and

(iii) re-introducing said Tregs and/or Teffs to the subject.