Deubiquitinases as pivotal regulators of T cell functions
Xiao-Dong Yang1, Shao-Cong Sun2,3()
1. Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China 2. Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX 77030, USA 3. The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
T cells efficiently respond to foreign antigens to mediate immune responses against infections but are tolerant to self-tissues. Defect in T cell activation is associated with severe immune deficiencies, whereas aberrant T cell activation contributes to the pathogenesis of diverse autoimmune and inflammatory diseases. An emerging mechanism that regulates T cell activation and tolerance is ubiquitination, a reversible process of protein modification that is counter-regulated by ubiquitinating enzymes and deubiquitinases (DUBs). DUBs are isopeptidases that cleave polyubiquitin chains and remove ubiquitin from target proteins, thereby controlling the magnitude and duration of ubiquitin signaling. It is now well recognized that DUBs are crucial regulators of T cell responses and serve as potential therapeutic targets for manipulating immune responses in the treatment of immunological disorders and cancer. This review will discuss the recent progresses regarding the functions of DUBs in T cells.
Salmond RJ, Filby A, Qureshi I, Caserta S, Zamoyska R. T-cell receptor proximal signaling via the Src-family kinases, Lck and Fyn, influences T-cell activation, differentiation, and tolerance. Immunol Rev 2009; 228(1): 9–22 https://doi.org/10.1111/j.1600-065X.2008.00745.x
pmid: 19290918
13
Ohashi PS. T-cell signalling and autoimmunity: molecular mechanisms of disease. Nat Rev Immunol 2002; 2(6): 427–438 https://doi.org/10.1038/nri822
pmid: 12093009
Kulathu Y, Komander D. Atypical ubiquitylation — the unexplored world of polyubiquitin beyond Lys48 and Lys63 linkages. Nat Rev Mol Cell Biol 2012; 13(8): 508–523 https://doi.org/10.1038/nrm3394
pmid: 22820888
Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK, Bernards R. A genomic and functional inventory of deubiquitinating enzymes. Cell 2005; 123(5): 773–786 https://doi.org/10.1016/j.cell.2005.11.007
pmid: 16325574
20
Abdul Rehman SA, Kristariyanto YA, Choi SY, Nkosi PJ, Weidlich S, Labib K, Hofmann K, Kulathu Y. MINDY-1 is a member of an evolutionarily conserved and structurally distinct new family of deubiquitinating enzymes. Mol Cell 2016; 63(1): 146–155 https://doi.org/10.1016/j.molcel.2016.05.009
pmid: 27292798
Klein L, Kyewski B, Allen PM, Hogquist KA. Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see). Nat Rev Immunol 2014; 14(6): 377–391 https://doi.org/10.1038/nri3667
pmid: 24830344
Reiley WW, Zhang M, Jin W, Losiewicz M, Donohue KB, Norbury CC, Sun SC. Regulation of T cell development by the deubiquitinating enzyme CYLD. Nat Immunol 2006; 7(4): 411–417 https://doi.org/10.1038/ni1315
pmid: 16501569
26
Sun SC. CYLD: a tumor suppressor deubiquitinase regulating NF-kB activation. Cell Death Differ 2010; 17(1): 25–34 doi:10.1038/cdd.2009.43
pmid: 19373246
27
Tsagaratou A, Trompouki E, Grammenoudi S, Kontoyiannis DL, Mosialos G. Thymocyte-specific truncation of the deubiquitinating domain of CYLD impairs positive selection in a NF-kB essential modulator-dependent manner. J Immunol 2010; 185(4): 2032–2043 https://doi.org/10.4049/jimmunol.0903919
pmid: 20644164
28
Reissig S, Hövelmeyer N, Tang Y, Weih D, Nikolaev A, Riemann M, Weih F, Waisman A. The deubiquitinating enzyme CYLD regulates the differentiation and maturation of thymic medullary epithelial cells. Immunol Cell Biol 2015; 93(6): 558–566 https://doi.org/10.1038/icb.2014.122
pmid: 25601276
29
Lee AJ, Zhou X, Chang M, Hunzeker J, Bonneau RH, Zhou D, Sun SC. Regulation of natural killer T-cell development by deubiquitinase CYLD. EMBO J 2010; 29(9): 1600–1612 https://doi.org/10.1038/emboj.2010.31
pmid: 20224552
Crosby CM, Kronenberg M. Invariant natural killer T cells: front line fighters in the war against pathogenic microbes. Immunogenetics 2016; 68(8): 639–648 https://doi.org/10.1007/s00251-016-0933-y
pmid: 27368411
32
Dashtsoodol N, Shigeura T, Aihara M, Ozawa R, Kojo S, Harada M, Endo TA, Watanabe T, Ohara O, Taniguchi M. Alternative pathway for the development of Va14+ NKT cells directly from CD4−CD8− thymocytes that bypasses the CD4+CD8+ stage. Nat Immunol 2017; 18(3): 274–282 https://doi.org/10.1038/ni.3668
pmid: 28135253
33
Drennan MB, Govindarajan S, Verheugen E, Coquet JM, Staal J, McGuire C, Taghon T, Leclercq G, Beyaert R, van Loo G, Lambrecht BN, Elewaut D. NKT sublineage specification and survival requires the ubiquitin-modifying enzyme TNFAIP3/A20. J Exp Med 2016; 213(10): 1973–1981 https://doi.org/10.1084/jem.20151065
pmid: 27551157
34
Lee YJ, Holzapfel KL, Zhu J, Jameson SC, Hogquist KA. Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells. Nat Immunol 2013; 14(11): 1146–1154 https://doi.org/10.1038/ni.2731
pmid: 24097110
35
Dufner A, Kisser A, Niendorf S, Basters A, Reissig S, Schönle A, Aichem A, Kurz T, Schlosser A, Yablonski D, Groettrup M, Buch T, Waisman A, Schamel WW, Prinz M, Knobeloch KP. The ubiquitin-specific protease USP8 is critical for the development and homeostasis of T cells. Nat Immunol 2015; 16(9): 950–960 https://doi.org/10.1038/ni.3230
pmid: 26214742
36
Adoro S, Park KH, Bettigole SE, Lis R, Shin HR, Seo H, Kim JH, Knobeloch KP, Shim JH, Glimcher LH. Post-translational control of T cell development by the ESCRT protein CHMP5. Nat Immunol 2017; 18(7): 780–790 https://doi.org/10.1038/ni.3764
pmid: 28553951
Thiefes A, Wolf A, Doerrie A, Grassl GA, Matsumoto K, Autenrieth I, Bohn E, Sakurai H, Niedenthal R, Resch K, Kracht M. The Yersinia enterocolitica effector YopP inhibits host cell signalling by inactivating the protein kinase TAK1 in the IL-1 signalling pathway. EMBO Rep 2006; 7(8): 838–844
pmid: 16845370
39
Reiley WW, Jin W, Lee AJ, Wright A, Wu X, Tewalt EF, Leonard TO, Norbury CC, Fitzpatrick L, Zhang M, Sun SC. Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. J Exp Med 2007; 204(6): 1475–1485 https://doi.org/10.1084/jem.20062694
pmid: 17548520
40
Schmid U, Stenzel W, Koschel J, Raptaki M, Wang X, Naumann M, Matuschewski K, Schlüter D, Nishanth G. The deubiquitinating enzyme cylindromatosis dampens CD8+ T cell responses and is a critical factor for experimental cerebral malaria and blood-brain barrier damage. Front Immunol 2017; 8: 27 https://doi.org/10.3389/fimmu.2017.00027
pmid: 28203236
41
Liu X, Li H, Zhong B, Blonska M, Gorjestani S, Yan M, Tian Q, Zhang DE, Lin X, Dong C. USP18 inhibits NF-kB and NFAT activation during Th17 differentiation by deubiquitinating the TAK1-TAB1 complex. J Exp Med 2013; 210(8): 1575–1590 https://doi.org/10.1084/jem.20122327
pmid: 23825189
Giordano M, Roncagalli R, Bourdely P, Chasson L, Buferne M, Yamasaki S, Beyaert R, van Loo G, Auphan-Anezin N, Schmitt-Verhulst AM, Verdeil G. The tumor necrosis factor α-induced protein 3 (TNFAIP3, A20) imposes a brake on antitumor activity of CD8 T cells. Proc Natl Acad Sci USA 2014; 111(30): 11115–11120 https://doi.org/10.1073/pnas.1406259111
pmid: 25024217
44
Just S, Nishanth G, Buchbinder JH, Wang X, Naumann M, Lavrik I, Schlüter D. A20 curtails primary but augments secondary CD8+ T cell responses in intracellular bacterial infection. Sci Rep 2016; 6(1): 39796 https://doi.org/10.1038/srep39796
pmid: 28004776
45
Onizawa M, Oshima S, Schulze-Topphoff U, Oses-Prieto JA, Lu T, Tavares R, Prodhomme T, Duong B, Whang MI, Advincula R, Agelidis A, Barrera J, Wu H, Burlingame A, Malynn BA, Zamvil SS, Ma A. The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis. Nat Immunol 2015; 16(6): 618–627 https://doi.org/10.1038/ni.3172
pmid: 25939025
46
Matsuzawa Y, Oshima S, Takahara M, Maeyashiki C, Nemoto Y, Kobayashi M, Nibe Y, Nozaki K, Nagaishi T, Okamoto R, Tsuchiya K, Nakamura T, Ma A, Watanabe M. TNFAIP3 promotes survival of CD4 T cells by restricting MTOR and promoting autophagy. Autophagy 2015; 11(7): 1052–1062 https://doi.org/10.1080/15548627.2015.1055439
pmid: 26043155
47
Linares JF, Duran A, Yajima T, Pasparakis M, Moscat J, Diaz-Meco MT. K63 polyubiquitination and activation of mTOR by the p62-TRAF6 complex in nutrient-activated cells. Mol Cell 2013; 51(3): 283–296 https://doi.org/10.1016/j.molcel.2013.06.020
pmid: 23911927
48
Park Y, Jin HS, Liu YC. Regulation of T cell function by the ubiquitin-specific protease USP9X via modulating the Carma1-Bcl10-Malt1 complex. Proc Natl Acad Sci USA 2013; 110(23): 9433–9438 https://doi.org/10.1073/pnas.1221925110
pmid: 23690623
49
Zou Q, Jin J, Hu H, Li HS, Romano S, Xiao Y, Nakaya M, Zhou X, Cheng X, Yang P, Lozano G, Zhu C, Watowich SS, Ullrich SE, Sun SC. USP15 stabilizes MDM2 to mediate cancer-cell survival and inhibit antitumor T cell responses. Nat Immunol 2014; 15(6): 562–570 https://doi.org/10.1038/ni.2885
pmid: 24777531
50
Hu H, Wang H, Xiao Y, Jin J, Chang JH, Zou Q, Xie X, Cheng X, Sun SC. Otud7b facilitates T cell activation and inflammatory responses by regulating Zap70 ubiquitination. J Exp Med 2016; 213(3): 399–414 https://doi.org/10.1084/jem.20151426
pmid: 26903241
51
Carpino N, Chen Y, Nassar N, Oh HW. The Sts proteins target tyrosine phosphorylated, ubiquitinated proteins within TCR signaling pathways. Mol Immunol 2009; 46(16): 3224–3231 https://doi.org/10.1016/j.molimm.2009.08.015
pmid: 19733910
52
Yang M, Chen T, Li X, Yu Z, Tang S, Wang C, Gu Y, Liu Y, Xu S, Li W, Zhang X, Wang J, Cao X. K33-linked polyubiquitination of Zap70 by Nrdp1 controls CD8+ T cell activation. Nat Immunol 2015; 16(12): 1253–1262 https://doi.org/10.1038/ni.3258
pmid: 26390156
53
Naik E, Webster JD, DeVoss J, Liu J, Suriben R, Dixit VM. Regulation of proximal T cell receptor signaling and tolerance induction by deubiquitinase Usp9X. J Exp Med 2014; 211(10): 1947–1955 https://doi.org/10.1084/jem.20140860
pmid: 25200027
54
Naik E, Dixit VM. Usp9X is required for lymphocyte activation and homeostasis through its control of ZAP70 ubiquitination and PKCb kinase activity. J Immunol 2016; 196(8): 3438–3451 https://doi.org/10.4049/jimmunol.1403165
pmid: 26936881
55
Garreau A, Blaize G, Argenty J, Rouquié N, Tourdès A, Wood SA, Saoudi A, Lesourne R. Grb2-mediated recruitment of USP9X to LAT enhances themis stability following thymic selection. J Immunol 2017; 199(8): 2758–2766 https://doi.org/10.4049/jimmunol.1700566
pmid: 28877990
56
Yamane H, Paul WE. Early signaling events that underlie fate decisions of naive CD4+ T cells toward distinct T-helper cell subsets. Immunol Rev 2013; 252(1): 12–23 PMID:23405892 https://doi.org/10.1111/imr.12032
57
Tu E, Chia CPZ, Chen W, Zhang D, Park SA, Jin W, Wang D, Alegre ML, Zhang YE, Sun L, Chen W. T Cell receptor-regulated TGF-β type I receptor expression determines T cell quiescence and activation. Immunity2018; 48(4): 745–759e6
Pan L, Chen Z, Wang L, Chen C, Li D, Wan H, Li B, Shi G. Deubiquitination and stabilization of T-bet by USP10. Biochem Biophys Res Commun 2014; 449(3): 289–294 https://doi.org/10.1016/j.bbrc.2014.05.037
pmid: 24845384
61
Rutz S, Kayagaki N, Phung QT, Eidenschenk C, Noubade R, Wang X, Lesch J, Lu R, Newton K, Huang OW, Cochran AG, Vasser M, Fauber BP, DeVoss J, Webster J, Diehl L, Modrusan Z, Kirkpatrick DS, Lill JR, Ouyang W, Dixit VM. Deubiquitinase DUBA is a post-translational brake on interleukin-17 production in T cells. Nature 2015; 518(7539): 417–421 https://doi.org/10.1038/nature13979
pmid: 25470037
62
Kayagaki N, Phung Q, Chan S, Chaudhari R, Quan C, O’Rourke KM, Eby M, Pietras E, Cheng G, Bazan JF, Zhang Z, Arnott D, Dixit VM. DUBA: a deubiquitinase that regulates type I interferon production. Science 2007; 318(5856): 1628–1632 https://doi.org/10.1126/science.1145918
pmid: 17991829
63
Han L, Yang J, Wang X, Wu Q, Yin S, Li Z, Zhang J, Xing Y, Chen Z, Tsun A, Li D, Piccioni M, Zhang Y, Guo Q, Jiang L, Bao L, Lv L, Li B. The E3 deubiquitinase USP17 is a positive regulator of retinoic acid-related orphan nuclear receptor gt (RORgt) in Th17 cells. J Biol Chem 2014; 289(37): 25546–25555 https://doi.org/10.1074/jbc.M114.565291
pmid: 25070893
64
Yang J, Xu P, Han L, Guo Z, Wang X, Chen Z, Nie J, Yin S, Piccioni M, Tsun A, Lv L, Ge S, Li B. Cutting edge: Ubiquitin-specific protease 4 promotes Th17 cell function under inflammation by deubiquitinating and stabilizing RORgt. J Immunol 2015; 194(9): 4094–4097 https://doi.org/10.4049/jimmunol.1401451
pmid: 25821221
65
He Z, Wang F, Ma J, Sen S, Zhang J, Gwack Y, Zhou Y, Sun Z. Ubiquitination of RORgt at lysine 446 limits Th17 differentiation by controlling coactivator recruitment. J Immunol 2016; 197(4): 1148–1158 https://doi.org/10.4049/jimmunol.1600548
pmid: 27430721
66
Zou Q, Jin J, Xiao Y, Zhou X, Hu H, Cheng X, Kazimi N, Ullrich SE, Sun SC. T cell intrinsic USP15 deficiency promotes excessive IFN-g production and an immunosuppressive tumor microenvironment in MCA-induced fibrosarcoma. Cell Reports 2015; 13(11): 2470–2479 https://doi.org/10.1016/j.celrep.2015.11.046
pmid: 26686633
67
Jin J, Xie X, Xiao Y, Hu H, Zou Q, Cheng X, Sun SC. Epigenetic regulation of the expression of Il12 and Il23 and autoimmune inflammation by the deubiquitinase Trabid. Nat Immunol 2016; 17(3): 259–268 https://doi.org/10.1038/ni.3347
pmid: 26808229
68
Kool M, van Loo G, Waelput W, De Prijck S, Muskens F, Sze M, van Praet J, Branco-Madeira F, Janssens S, Reizis B, Elewaut D, Beyaert R, Hammad H, Lambrecht BN. The ubiquitin-editing protein A20 prevents dendritic cell activation, recognition of apoptotic cells, and systemic autoimmunity. Immunity 2011; 35(1): 82–96 https://doi.org/10.1016/j.immuni.2011.05.013
pmid: 21723156
69
Hammer GE, Turer EE, Taylor KE, Fang CJ, Advincula R, Oshima S, Barrera J, Huang EJ, Hou B, Malynn BA, Reizis B, DeFranco A, Criswell LA, Nakamura MC, Ma A. Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis. Nat Immunol 2011; 12(12): 1184–1193 https://doi.org/10.1038/ni.2135
pmid: 22019834
70
Liang J, Huang HI, Benzatti FP, Karlsson AB, Zhang JJ, Youssef N, Ma A, Hale LP, Hammer GE. Inflammatory Th1 and Th17 in the intestine are each driven by functionally specialized dendritic cells with distinct requirements for MyD88. Cell Reports 2016; 17(5): 1330–1343 https://doi.org/10.1016/j.celrep.2016.09.091
pmid: 27783947
71
Wang L, Hong B, Jiang X, Jones L, Chen SY, Huang XF. A20 controls macrophage to elicit potent cytotoxic CD4+ T cell response. PLoS One 2012; 7(11): e48930 https://doi.org/10.1371/journal.pone.0048930
pmid: 23145026
Zhao Y, Thornton AM, Kinney MC, Ma CA, Spinner JJ, Fuss IJ, Shevach EM, Jain A. The deubiquitinase CYLD targets Smad7 protein to regulate transforming growth factor b (TGF-b) signaling and the development of regulatory T cells. J Biol Chem 2011; 286(47): 40520–40530 https://doi.org/10.1074/jbc.M111.292961
pmid: 21931165
76
Reissig S, Hövelmeyer N, Weigmann B, Nikolaev A, Kalt B, Wunderlich TF, Hahn M, Neurath MF, Waisman A. The tumor suppressor CYLD controls the function of murine regulatory T cells. J Immunol 2012; 189(10): 4770–4776 https://doi.org/10.4049/jimmunol.1201993
pmid: 23066153
77
Fischer JC, Otten V, Kober M, Drees C, Rosenbaum M, Schmickl M, Heidegger S, Beyaert R, van Loo G, Li XC, Peschel C, Schmidt-Supprian M, Haas T, Spoerl S, Poeck H. A20 restrains thymic regulatory T cell development. J Immunol 2017; 199(7): 2356–2365 https://doi.org/10.4049/jimmunol.1602102
pmid: 28842469
78
Chang JH, Xiao Y, Hu H, Jin J, Yu J, Zhou X, Wu X, Johnson HM, Akira S, Pasparakis M, Cheng X, Sun SC. Ubc13 maintains the suppressive function of regulatory T cells and prevents their conversion into effector-like T cells. Nat Immunol 2012; 13(5): 481–490 https://doi.org/10.1038/ni.2267
pmid: 22484734
van Loosdregt J, Fleskens V, Fu J, Brenkman AB, Bekker CP, Pals CE, Meerding J, Berkers CR, Barbi J, Gröne A, Sijts AJ, Maurice MM, Kalkhoven E, Prakken BJ, Ovaa H, Pan F, Zaiss DM, Coffer PJ. Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 increases Treg-cell-suppressive capacity. Immunity 2013; 39(2): 259–271 https://doi.org/10.1016/j.immuni.2013.05.018
pmid: 23973222
81
Wang L, Kumar S, Dahiya S, Wang F, Wu J, Newick K, Han R, Samanta A, Beier UH, Akimova T, Bhatti TR, Nicholson B, Kodrasov MP, Agarwal S, Sterner DE, Gu W, Weinstock J, Butt TR, Albelda SM, Hancock WW. Ubiquitin-specific protease-7 inhibition impairs Tip60-dependent Foxp3+ T-regulatory cell function and promotes antitumor immunity. EBioMedicine 2016; 13: 99–112 https://doi.org/10.1016/j.ebiom.2016.10.018
pmid: 27769803
82
Xiao Y, Nagai Y, Deng G, Ohtani T, Zhu Z, Zhou Z, Zhang H, Ji MQ, Lough JW, Samanta A, Hancock WW, Greene MI. Dynamic interactions between TIP60 and p300 regulate FOXP3 function through a structural switch defined by a single lysine on TIP60. Cell Reports 2014; 7(5): 1471–1480 https://doi.org/10.1016/j.celrep.2014.04.021
pmid: 24835996
83
Turnbull AP, Ioannidis S, Krajewski WW, Pinto-Fernandez A, Heride C, Martin ACL, Tonkin LM, Townsend EC, Buker SM, Lancia DR, Caravella JA, Toms AV, Charlton TM, Lahdenranta J, Wilker E, Follows BC, Evans NJ, Stead L, Alli C, Zarayskiy VV, Talbot AC, Buckmelter AJ, Wang M, McKinnon CL, Saab F, McGouran JF, Century H, Gersch M, Pittman MS, Marshall CG, Raynham TM, Simcox M, Stewart LMD, McLoughlin SB, Escobedo JA, Bair KW, Dinsmore CJ, Hammonds TR, Kim S, Urbé S, Clague MJ, Kessler BM, Komander D. Molecular basis of USP7 inhibition by selective small-molecule inhibitors. Nature 2017; 550(7677): 481–486 https://doi.org/10.1038/nature24451
pmid: 29045389
84
Kategaya L, Di Lello P, Rougé L, Pastor R, Clark KR, Drummond J, Kleinheinz T, Lin E, Upton JP, Prakash S, Heideker J, McCleland M, Ritorto MS, Alessi DR, Trost M, Bainbridge TW, Kwok MCM, Ma TP, Stiffler Z, Brasher B, Tang Y, Jaishankar P, Hearn BR, Renslo AR, Arkin MR, Cohen F, Yu K, Peale F, Gnad F, Chang MT, Klijn C, Blackwood E, Martin SE, Forrest WF, Ernst JA, Ndubaku C, Wang X, Beresini MH, Tsui V, Schwerdtfeger C, Blake RA, Murray J, Maurer T, Wertz IE. USP7 small-molecule inhibitors interfere with ubiquitin binding. Nature 2017; 550(7677): 534–538 https://doi.org/10.1038/nature24006
pmid: 29045385