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Immune Regulation by Ubiquitin Tagging as Checkpoint Code

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Book cover Emerging Concepts Targeting Immune Checkpoints in Cancer and Autoimmunity

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 410))

Abstract

The immune system is equipped with effective machinery to mobilize its activation to defend invading microorganisms, and at the same time, to refrain from attacking its own tissues to maintain immune tolerance. The balance of activation and tolerance is tightly controlled by diverse mechanisms, since breakdown of tolerance could result in disastrous consequences such as the development of autoimmune diseases. One of the mechanisms is by the means of protein ubiquitination, which involves the process of tagging a small peptide ubiquitin to protein substrates. E3 ubiquitin ligases are responsible for catalyzing the final step of ubiquitin–substrate conjugation by specifically recognizing substrates to determine their fates of degradation or functional modification. The ubiquitination process is reversible, which is carried out by deubiquitinating enzymes to release the ubiquitin molecule from the conjugated substrates. Protein ubiquitination and deubiquitination serve as checkpoint codes in many key steps of lymphocyte regulation including the development, activation, differentiation, and tolerance induction. In this chapter, we will discuss a few E3 ligases and deubiquitinating enzymes that are important in controlling immune responses, with emphasis on their roles in T cells.

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References

  • Abbas AK, Benoist C, Bluestone JA, Campbell DJ, Ghosh S, Hori S, Jiang S, Kuchroo VK, Mathis D, Roncarolo MG, Rudensky A, Sakaguchi S, Shevach EM, Vignali DA, Ziegler SF (2013) Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol 14(4):307–308. doi:10.1038/ni.2554

    Article  CAS  PubMed  Google Scholar 

  • Aki D, Zhang W, Liu YC (2015) The E3 ligase Itch in immune regulation and beyond. Immunol Rev 266(1):6–26. doi:10.1111/imr.12301

    Article  CAS  PubMed  Google Scholar 

  • Akiyama T, Maeda S, Yamane S, Ogino K, Kasai M, Kajiura F, Matsumoto M, Inoue J (2005) Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science 308(5719):248–251. doi:10.1126/science.1105677

  • Anandasabapathy N, Ford GS, Bloom D, Holness C, Paragas V, Seroogy C, Skrenta H, Hollenhorst M, Fathman CG, Soares L (2003) GRAIL: An E3 ubiquitin ligase that inhibits cytokine gene transcription is expressed in anergic CD4(+) T cells. Immunity 18(4):535–547. doi:10.1016/S1074-7613(03)00084-0

  • Bachmaier K, Krawczyk C, Kozieradzki I, Kong YY, Sasaki T, Oliveira-dos-Santos A, Mariathasan S, Bouchard D, Wakeham A, Itie A, Le J, Ohashi PS, Sarosi I, Nishina H, Lipkowitz S, Penninger JM (2000) Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 403(6766):211–216. doi:10.1038/35003228

    Article  CAS  PubMed  Google Scholar 

  • Beal AM, Ramos-Hernandez N, Riling CR, Nowelsky EA, Oliver PM (2011) TGF-beta induces the expression of the adaptor Ndfip1 to silence IL-4 production during iTreg cell differentiation. Nat Immunol 13(1):77–85. doi:10.1038/ni.2154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ben-Shoshan J, Maysel-Auslender S, Mor A, Keren G, George J (2008) Hypoxia controls CD4 + CD25 + regulatory T-cell homeostasis via hypoxia-inducible factor-1alpha. Eur J Immunol 38(9):2412–2418. doi:10.1002/eji.200838318

    Article  CAS  PubMed  Google Scholar 

  • Bignell GR, Warren W, Seal S, Takahashi M, Rapley E, Barfoot R, Green H, Brown C, Biggs PJ, Lakhani SR, Jones C, Hansen J, Blair E, Hofmann B, Siebert R, Turner G, Evans DG, Schrander-Stumpel C, Beemer FA, van Den Ouweland A, Halley D, Delpech B, Cleveland MG, Leigh I, Leisti J, Rasmussen S (2000) Identification of the familial cylindromatosis tumour-suppressor gene. Nat Genet 25(2):160–165. doi:10.1038/76006

    Article  CAS  PubMed  Google Scholar 

  • Boone DL, Turer EE, Lee EG, Ahmad R-C, Wheeler MT, Tsui C, Hurley P, Chien M, Chai S, Hitotsumatsu O (2004) The ubiquitin-modifying enzyme A20 is required for termination of toll-like receptor responses. Nat Immunol 5(10):1052–1060

    Article  CAS  Google Scholar 

  • Bowen S, Gill M, Lee DA, Fisher G, Geronemus RG, Vazquez ME, Celebi JT (2005) Mutations in the CYLD gene in Brooke-Spiegler syndrome, familial cylindromatosis, and multiple familial trichoepithelioma: lack of genotype-phenotype correlation. J Invest Dermatol 124(5):919–920. doi:10.1111/j.0022-202X.2005.23688.x

    Article  CAS  PubMed  Google Scholar 

  • Bros M, Dexheimer N, Besche V, Masri J, Trojandt S, Hovelmeyer N, Reissig S, Massoumi R, Grabbe S, Waisman A, Reske-Kunz AB (2010) Mutated cylindromatosis gene affects the functional state of dendritic cells. Eur J Immunol 40(10):2848–2857. doi:10.1002/eji.200939285

    Article  PubMed  Google Scholar 

  • Cao X, Cai SF, Fehniger TA, Song J, Collins LI, Piwnica-Worms DR, Ley TJ (2007) Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 27(4):635–646. doi:10.1016/j.immuni.2007.08.014

    Article  CAS  PubMed  Google Scholar 

  • Cejas PJ, Walsh MC, Pearce EL, Han D, Harms GM, Artis D, Turka LA, Choi Y (2010) TRAF6 inhibits Th17 differentiation and TGF-beta-mediated suppression of IL-2. Blood 115(23):4750–4757. doi:10.1182/blood-2009-09-242768

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chiang YJ, Kole HK, Brown K, Naramura M, Fukuhara S, Hu RJ, Jang IK, Gutkind JS, Shevach E, Gu H (2000) Cbl-b regulates the CD28 dependence of T-cell activation. Nature 403(6766):216–220. doi:10.1038/35003235

    Article  CAS  PubMed  Google Scholar 

  • Chiang JY, Jang IK, Hodes R, Gu H (2007) Ablation of Cbl-b provides protection against transplanted and spontaneous tumors. J Clin Invest 117(4):1029–1036. doi:10.1172/JCI29472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chu Y, Vahl JC, Kumar D, Heger K, Bertossi A, Wojtowicz E, Soberon V, Schenten D, Mack B, Reutelshofer M, Beyaert R, Amann K, van Loo G, Schmidt-Supprian M (2011) B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice. Blood 117(7):2227–2236. doi:10.1182/blood-2010-09-306019

    Article  CAS  PubMed  Google Scholar 

  • Chu Y, Soberon V, Glockner L, Beyaert R, Massoumi R, van Loo G, Krappmann D, Schmidt-Supprian M (2012) A20 and CYLD do not share significant overlapping functions during B cell development and activation. J Immunol 189(9):4437–4443

    Article  CAS  Google Scholar 

  • Clambey ET, McNamee EN, Westrich JA, Glover LE, Campbell EL, Jedlicka P, de Zoeten EF, Cambier JC, Stenmark KR, Colgan SP, Eltzschig HK (2012) Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci USA 109(41):E2784–E2793. doi:10.1073/pnas.1202366109

    Article  PubMed  Google Scholar 

  • Collison LW, Pillai MR, Chaturvedi V, Vignali DA (2009) Regulatory T cell suppression is potentiated by target T cells in a cell contact, IL-35- and IL-10-dependent manner. J Immunol 182(10):6121–6128. doi:10.4049/jimmunol.0803646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coornaert B, Baens M, Heyninck K, Bekaert T, Haegman M, Staal J, Sun L, Chen ZJ, Marynen P, Beyaert R (2008) T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20. Nat Immunol 9(3):263–271. doi:10.1038/ni1561

    Article  CAS  PubMed  Google Scholar 

  • Crotty S (2011) Follicular Helper CD4 T Cells (T-FH). Annu Rev Immunol 29(29):621–663

    Article  CAS  Google Scholar 

  • Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, Bordman Z, Fu J, Kim Y, Yen HR, Luo W, Zeller K, Shimoda L, Topalian SL, Semenza GL, Dang CV, Pardoll DM, Pan F (2011) Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 146(5):772–784. doi:10.1016/j.cell.2011.07.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Wilde K, Martens A, Lambrecht S, Jacques P, Drennan MB, Debusschere K, Govindarajan S, Coudenys J, Verheugen E, Windels F, Catrysse L, Lories R, McGonagle D, Beyaert R, van Loo G, Elewaut D (2017) A20 inhibition of STAT1 expression in myeloid cells: a novel endogenous regulatory mechanism preventing development of enthesitis. Ann Rheum Dis 76(3):585–592. doi:10.1136/annrheumdis-2016-209454

    Article  CAS  PubMed  Google Scholar 

  • Delgoffe GM, Woo SR, Turnis ME, Gravano DM, Guy C, Overacre AE, Bettini ML, Vogel P, Finkelstein D, Bonnevier J, Workman CJ, Vignali DA (2013) Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 501(7466):252–256. doi:10.1038/nature12428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Doherty M, Osborne DG, Browning DL, Parker DC, Wetzel SA (2010) Anergic CD4 + T cells form mature immunological synapses with enhanced accumulation of c-Cbl and Cbl-b. J Immunol 184(7):3598–3608. doi:10.4049/jimmunol.0902285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duong BH, Onizawa M, Oses-Prieto JA, Advincula R, Burlingame A, Malynn BA, Ma A (2015) A20 restricts ubiquitination of pro-interleukin-1beta protein complexes and suppresses NLRP3 inflammasome activity. Immunity 42(1):55–67. doi:10.1016/j.immuni.2014.12.031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duwel M, Welteke V, Oeckinghaus A, Baens M, Kloo B, Ferch U, Darnay BG, Ruland J, Marynen P, Krappmann D (2009) A20 negatively regulates T cell receptor signaling to NF-kappaB by cleaving Malt1 ubiquitin chains. J Immunol 182(12):7718–7728. doi:10.4049/jimmunol.0803313

    Article  CAS  PubMed  Google Scholar 

  • Enzler T, Chang X, Facchinetti V, Melino G, Karin M, Su B, Gallagher E (2009) MEKK1 binds HECT E3 ligase Itch by its amino-terminal RING motif to regulate Th2 cytokine gene expression. J Immunol 183(6):3831–3838. doi:10.4049/jimmunol.0803412

    Article  CAS  PubMed  Google Scholar 

  • Fahlen L, Read S, Gorelik L, Hurst SD, Coffman RL, Flavell RA, Powrie F (2005) T cells that cannot respond to TGF-beta escape control by CD4(+)CD25(+) regulatory T cells. J Exp Med 201(5):737–746. doi:10.1084/jem.20040685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fang D, Wang HY, Fang N, Altman Y, Elly C, Liu YC (2001) Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells. J Biol Chem 276(7):4872–4878. doi:10.1074/jbc.M008901200

    Article  CAS  PubMed  Google Scholar 

  • Fang D, Elly C, Gao B, Fang N, Altman Y, Joazeiro C, Hunter T, Copeland N, Jenkins N, Liu YC (2002) Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation. Nat Immunol 3(3):281–287. doi:10.1038/ni763

    Article  CAS  PubMed  Google Scholar 

  • Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4 + CD25 + regulatory T cells. Nat Immunol 4(4):330–336. doi:10.1038/ni904

    Article  CAS  PubMed  Google Scholar 

  • Fraile JM, Quesada V, Rodriguez D, Freije JM, Lopez-Otin C (2012) Deubiquitinases in cancer: new functions and therapeutic options. Oncogene 31(19):2373–2388. doi:10.1038/onc.2011.443

    Article  CAS  PubMed  Google Scholar 

  • Gallagher E, Gao M, Liu YC, Karin M (2006) Activation of the E3 ubiquitin ligase Itch through a phosphorylation-induced conformational change. Proc Natl Acad Sci USA 103(6):1717–1722

    Article  CAS  Google Scholar 

  • Gao M, Labuda T, Xia Y, Gallagher E, Fang D, Liu YC, Karin M (2004) Jun turnover is controlled through JNK-dependent phosphorylation of the E3 ligase itch. Science 306(5694):271–275

    Article  CAS  Google Scholar 

  • Gavin MA, Rasmussen JP, Fontenot JD, Vasta V, Manganiello VC, Beavo JA, Rudensky AY (2007) Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445(7129):771–775. doi:10.1038/nature05543

    Article  CAS  PubMed  Google Scholar 

  • Gerlach B, Cordier SM, Schmukle AC, Emmerich CH, Rieser E, Haas TL, Webb AI, Rickard JA, Anderton H, Wong WW, Nachbur U, Gangoda L, Warnken U, Purcell AW, Silke J, Walczak H (2011) Linear ubiquitination prevents inflammation and regulates immune signalling. Nature 471(7340):591–596. doi:10.1038/nature09816

    Article  CAS  PubMed  Google Scholar 

  • Goetz B, An W, Mohapatra B, Zutshi N, Iseka F, Storck MD, Meza J, Sheinin Y, Band V, Band H (2016) A novel CBL-Bflox/flox mouse model allows tissue-selective fully conditional CBL/CBL-B double-knockout: CD4-Cre mediated CBL/CBL-B deletion occurs in both T-cells and hematopoietic stem cells. Oncotarget 7(32):51107–51123

    Article  Google Scholar 

  • Gronski MA, Boulter JM, Moskophidis D, Nguyen LT, Holmberg K, Elford AR, Deenick EK, Kim HO, Penninger JM, Odermatt B, Gallimore A, Gascoigne NR, Ohashi PS (2004) TCR affinity and negative regulation limit autoimmunity. Nat Med 10(11):1234–1239. doi:10.1038/nm1114

    Article  CAS  PubMed  Google Scholar 

  • Gruber T, Hermann-Kleiter N, Hinterleitner R, Fresser F, Schneider R, Gastl G, Penninger JM, Baier G (2009) PKC-theta modulates the strength of T cell responses by targeting Cbl-b for ubiquitination and degradation. Sci Signal 2(76):ra30. doi:10.1126/scisignal.2000046

  • Gruber T, Hinterleitner R, Hermann-Kleiter N, Meisel M, Kleiter I, Wang CM, Viola A, Pfeifhofer-Obermair C, Baier G (2013) Cbl-b mediates TGF beta sensitivity by downregulating inhibitory SMAD7 in primary T cells. J Mol Cell Biol 5(6):358–368

    Article  CAS  Google Scholar 

  • Guo H, Qiao G, Ying H, Li Z, Zhao Y, Liang Y, Yang L, Lipkowitz S, Penninger JM, Langdon WY, Zhang J (2012) E3 ubiquitin ligase Cbl-b regulates Pten via Nedd4 in T cells independently of its ubiquitin ligase activity. Cell Rep 1(5):472–482. doi:10.1016/j.celrep.2012.04.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haas TL, Emmerich CH, Gerlach B, Schmukle AC, Cordier SM, Rieser E, Feltham R, Vince J, Warnken U, Wenger T, Koschny R, Komander D, Silke J, Walczak H (2009) Recruitment of the linear ubiquitin chain assembly complex stabilizes the TNF-R1 signaling complex and is required for TNF-mediated gene induction. Mol Cell 36(5):831–844. doi:10.1016/j.molcel.2009.10.013

    Article  CAS  PubMed  Google Scholar 

  • 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 (2011) Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis. Nat Immunol 12(12):1184–1193. doi:10.1038/ni.2135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hanlon A, Jang S, Salgame P (2005) Cbl-b differentially regulates activation-induced apoptosis in T helper 1 and T helper 2 cells. Immunology 116(4):507–512. doi:10.1111/j.1365-2567.2005.02252.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harada Y, Harada Y, Elly C, Ying G, Paik JH, DePinho RA, Liu YC (2010) Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells. J Exp Med 207(7):1381–1391. doi:10.1084/jem.20100004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heissmeyer V, Rao A (2004) E3 ligases in T cell anergy–turning immune responses into tolerance. Sci STKE 2004(241):pe29. doi:10.1126/stke.2412004pe29

  • Heissmeyer V, Macian F, Im SH, Varma R, Feske S, Venuprasad K, Gu H, Liu YC, Dustin ML, Rao A (2004) Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins. Nat Immunol 5(3):255–265

    Article  CAS  Google Scholar 

  • Hinterleitner R, Gruber T, Pfeifhofer-Obermair C, Lutz-Nicoladoni C, Tzankov A, Schuster M, Penninger JM, Loibner H, Lametschwandtner G, Wolf D, Baier G (2012) Adoptive transfer of siRNA Cblb-silenced CD8 + T lymphocytes augments tumor vaccine efficacy in a B16 melanoma model. PLoS ONE 7(9):e44295. doi:10.1371/journal.pone.0044295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hitotsumatsu O, Ahmad RC, Tavares R, Wang M, Philpott D, Turer EE, Lee BL, Shiffin N, Advincula R, Malynn BA, Werts C, Ma A (2008) The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals. Immunity 28(3):381–390. doi:10.1016/j.immuni.2008.02.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057–1061. doi:10.1126/science.1079490

    Article  CAS  Google Scholar 

  • Hovelmeyer N, Wunderlich FT, Massoumi R, Jakobsen CG, Song J, Worns MA, Merkwirth C, Kovalenko A, Aumailley M, Strand D, Bruning JC, Galle PR, Wallach D, Fassler R, Waisman A (2007) Regulation of B cell homeostasis and activation by the tumor suppressor gene CYLD. J Exp Med 204(11):2615–2627. doi:10.1084/jem.20070318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hovelmeyer N, Reissig S, Xuan NT, Adams-Quack P, Lukas D, Nikolaev A, Schluter D, Waisman A (2011) A20 deficiency in B cells enhances B-cell proliferation and results in the development of autoantibodies. Eur J Immunol 41(3):595–601. doi:10.1002/eji.201041313

    Article  CAS  PubMed  Google Scholar 

  • Hoyne GF, Flening E, Yabas M, Teh C, Altin JA, Randall K, Thien CB, Langdon WY, Goodnow CC (2011) Visualizing the role of Cbl-b in control of islet-reactive CD4 T cells and susceptibility to type 1 diabetes. J Immunol 186(4):2024–2032. doi:10.4049/jimmunol.1002296

    Article  CAS  PubMed  Google Scholar 

  • Hsu TS, Hsiao HW, Wu PJ, Liu WH, Lai MZ (2014) Deltex1 promotes protein kinase Ctheta degradation and sustains Casitas B-lineage lymphoma expression. J Immunol 193(4):1672–1680. doi:10.4049/jimmunol.1301416

    Article  CAS  PubMed  Google Scholar 

  • Hu J, Wang G, Liu X, Zhou L, Jiang M, Yang L (2014) A20 is critical for the induction of Pam3CSK4-tolerance in monocytic THP-1 cells. PLoS ONE 9(1):e87528. doi:10.1371/journal.pone.0087528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang F, Kitaura Y, Jang I, Naramura M, Kole HH, Liu L, Qin H, Schlissel MS, Gu H (2006) Establishment of the major compatibility complex-dependent development of CD4 + and CD8 + T cells by the Cbl family proteins. Immunity 25(4):571–581. doi:10.1016/j.immuni.2006.08.021

    Article  CAS  PubMed  Google Scholar 

  • Huang H, Jeon MS, Liao L, Yang C, Elly C, Yates JR 3rd, Liu YC (2010) K33-linked polyubiquitination of T cell receptor-zeta regulates proteolysis-independent T cell signaling. Immunity 33(1):60–70. doi:10.1016/j.immuni.2010.07.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hustad CM, Perry WL, Siracusa LD, Rasberry C, Cobb L, Cattanach BM, Kovatch R, Copeland NG, Jenkins NA (1995) Molecular genetic characterization of six recessive viable alleles of the mouse agouti locus. Genetics 140(1):255–265

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hutti JE, Turk BE, Asara JM, Ma A, Cantley LC, Abbott DW (2007) IkappaB kinase beta phosphorylates the K63 deubiquitinase A20 to cause feedback inhibition of the NF-kappaB pathway. Mol Cell Biol 27(21):7451–7461. doi:10.1128/MCB.01101-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ikeda F, Deribe YL, Skanland SS, Stieglitz B, Grabbe C, Franz-Wachtel M, van Wijk SJ, Goswami P, Nagy V, Terzic J, Tokunaga F, Androulidaki A, Nakagawa T, Pasparakis M, Iwai K, Sundberg JP, Schaefer L, Rittinger K, Macek B, Dikic I (2011) SHARPIN forms a linear ubiquitin ligase complex regulating NF-kappaB activity and apoptosis. Nature 471(7340):637–641. doi:10.1038/nature09814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr (2001) HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292(5516):464–468. doi:10.1126/science.1059817

    Article  CAS  PubMed  Google Scholar 

  • Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, von Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292(5516):468–472. doi:10.1126/science.1059796

    Article  CAS  PubMed  Google Scholar 

  • Jackson PK, Eldridge AG, Freed E, Furstenthal L, Hsu JY, Kaiser BK, Reimann JD (2000) The lore of the RINGs: substrate recognition and catalysis by ubiquitin ligases. Trends Cell Biol 10(10):429–439. doi:10.1016/S0962-8924(00)01834-1

  • Jeon MS, Atfield A, Venuprasad K, Krawczyk C, Sarao R, Elly C, Yang C, Arya S, Bachmaier K, Su L, Bouchard D, Jones R, Gronski M, Ohashi P, Wada T, Bloom D, Fathman CG, Liu YC, Penninger JM (2004) Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction. Immunity 21(2):167–177. doi:10.1016/j.immuni.2004.07.013

    Article  CAS  PubMed  Google Scholar 

  • Jin W, Reiley WR, Lee AJ, Wright A, Wu X, Zhang M, Sun SC (2007) Deubiquitinating enzyme CYLD regulates the peripheral development and naive phenotype maintenance of B cells. J Biol Chem 282(21):15884–15893. doi:10.1074/jbc.M609952200

    Article  CAS  PubMed  Google Scholar 

  • Jin HS, Park Y, Elly C, Liu YC (2013) Itch expression by Treg cells controls Th2 inflammatory responses. J Clin Invest 123(11):4923–4934. doi:10.1172/JCI69355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaelin WG, Jr., Maher ER (1998) The VHL tumour-suppressor gene paradigm. Trends Genet 14(10):423–426. doi:10.1016/S0168-9525(98)01558-3

  • Kamura T, Koepp DM, Conrad MN, Skowyra D, Moreland RJ, Iliopoulos O, Lane WS, Kaelin WG, Jr., Elledge SJ, Conaway RC, Harper JW, Conaway JW (1999) Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science 284(5414):657–661. doi:10.1126/science.284.5414.657

  • Karwacz K, Bricogne C, MacDonald D, Arce F, Bennett CL, Collins M, Escors D (2011) PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8 + T cells. EMBO Mol Med 3(10):581–592. doi:10.1002/emmm.201100165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kathania M, Khare P, Zeng M, Cantarel B, Zhang H, Ueno H, Venuprasad K (2016) Itch inhibits IL-17-mediated colon inflammation and tumorigenesis by ROR-gammat ubiquitination. Nat Immunol 17(8):997–1004. doi:10.1038/ni.3488

    Article  CAS  PubMed  Google Scholar 

  • King CG, Kobayashi T, Cejas PJ, Kim T, Yoon K, Kim GK, Chiffoleau E, Hickman SP, Walsh PT, Turka LA, Choi Y (2006) TRAF6 is a T cell-intrinsic negative regulator required for the maintenance of immune homeostasis. Nat Med 12(9):1088–1092. doi:10.1038/nm1449

    Article  CAS  PubMed  Google Scholar 

  • King CG, Buckler JL, Kobayashi T, Hannah JR, Bassett G, Kim T, Pearce EL, Kim GG, Turka LA, Choi Y (2008) Cutting edge: requirement for TRAF6 in the induction of T cell anergy. J Immunol 180(1):34–38

    Article  CAS  Google Scholar 

  • Kojo S, Elly C, Harada Y, Langdon WY, Kronenberg M, Liu YC (2009) Mechanisms of NKT cell anergy induction involve Cbl-b-promoted monoubiquitination of CARMA1. Proc Natl Acad Sci USA 106(42):17847–17851. doi:10.1073/pnas.0904078106

    Article  PubMed  Google Scholar 

  • Komander D, Rape M (2012) The ubiquitin code. Annu Rev Biochem 81:203–229. doi:10.1146/annurev-biochem-060310-170328

    Article  CAS  PubMed  Google Scholar 

  • Komander D, Reyes-Turcu F, Licchesi JD, Odenwaelder P, Wilkinson KD, Barford D (2009) Molecular discrimination of structurally equivalent Lys 63-linked and linear polyubiquitin chains. EMBO Rep 10(5):466–473. doi:10.1038/embor.2009.55

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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 (2011) The ubiquitin-editing protein A20 prevents dendritic cell activation, recognition of apoptotic cells, and systemic autoimmunity. Immunity 35(1):82–96. doi:10.1016/j.immuni.2011.05.013

    Article  CAS  PubMed  Google Scholar 

  • Kovalenko A, Chable-Bessia C, Cantarella G, Israel A, Wallach D, Courtois G (2003) The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination. Nature 424(6950):801–805. doi:10.1038/nature01802

    Article  CAS  PubMed  Google Scholar 

  • Krawczyk C, Bachmaier K, Sasaki T, Jones RG, Snapper SB, Bouchard D, Kozieradzki I, Ohashi PS, Alt FW, Penninger JM (2000) Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cells. Immunity 13(4):463–473

    Article  CAS  Google Scholar 

  • Krawczyk CM, Jones RG, Atfield A, Bachmaier K, Arya S, Odermatt B, Ohashi PS, Penninger JM (2005) Differential control of CD28-regulated in vivo immunity by the E3 ligase Cbl-b. J Immunol 174(3):1472–1478

    Article  CAS  Google Scholar 

  • Layman AAK, Sprout SL, Phillips D, Oliver PM (2017) Ndfip1 restricts Th17 cell potency by limiting lineage stability and proinflammatory cytokine production. Sci Rep 7:39649. doi:10.1038/srep39649

    Article  CAS  PubMed  Google Scholar 

  • Lee EG, Boone DL, Chai S, Libby SL, Chien M, Lodolce JP, Ma A (2000) Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 289(5488):2350–2354

    Article  CAS  Google Scholar 

  • Lee AJ, Zhou X, Chang M, Hunzeker J, Bonneau RH, Zhou D, Sun SC (2010) Regulation of natural killer T-cell development by deubiquitinase CYLD. EMBO J 29(9):1600–1612. doi:10.1038/emboj.2010.31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee JH, Elly C, Park Y, Liu YC (2015) E3 Ubiquitin Ligase VHL Regulates Hypoxia-Inducible Factor-1alpha to Maintain Regulatory T Cell Stability and Suppressive Capacity. Immunity 42(6):1062–1074. doi:10.1016/j.immuni.2015.05.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li D, Gal I, Vermes C, Alegre ML, Chong AS, Chen L, Shao Q, Adarichev V, Xu X, Koreny T, Mikecz K, Finnegan A, Glant TT, Zhang J (2004) Cutting edge: Cbl-b: one of the key molecules tuning CD28- and CTLA-4-mediated T cell costimulation. J Immunol 173(12):7135–7139

    Article  CAS  Google Scholar 

  • Li Y, Zhang P, Wang C, Han C, Meng J, Liu X, Xu S, Li N, Wang Q, Shi X (2013) Immune responsive gene 1 (IRG1) promotes endotoxin tolerance by increasing A20 expression in macrophages through reactive oxygen species. J Biol Chem 288(23):16225–16234

    Article  CAS  Google Scholar 

  • Li M, Shi X, Qian T, Li J, Tian Z, Ni B, Hao F (2015) A20 overexpression alleviates pristine-induced lupus nephritis by inhibiting the NF-kappaB and NLRP3 inflammasome activation in macrophages of mice. Int J Clin Exp Med 8(10):17430–17440

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li MY, Zhu M, Linghu EQ, Feng F, Zhu B, Wu C, Guo MZ (2016) Interleukin-13 suppresses interleukin-10 via inhibiting A20 in peripheral B cells of patients with food allergy. Oncotarget 7(48):79914–79924. doi:10.18632/oncotarget.13107

    Article  PubMed  PubMed Central  Google Scholar 

  • Liang B, Workman C, Lee J, Chew C, Dale BM, Colonna L, Flores M, Li N, Schweighoffer E, Greenberg S, Tybulewicz V, Vignali D, Clynes R (2008) Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II. J Immunol 180(9):5916–5926

    Article  CAS  Google Scholar 

  • Liu J, Han C, Xie B, Wu Y, Liu S, Chen K, Xia M, Zhang Y, Song L, Li Z, Zhang T, Ma F, Wang Q, Wang J, Deng K, Zhuang Y, Wu X, Yu Y, Xu T, Cao X (2014) Rhbdd3 controls autoimmunity by suppressing the production of IL-6 by dendritic cells via K27-linked ubiquitination of the regulator NEMO. Nat Immunol 15(7):612–622. doi:10.1038/ni.2898

    Article  CAS  PubMed  Google Scholar 

  • Loeser S, Penninger JM (2007) Regulation of peripheral T cell tolerance by the E3 ubiquitin ligase Cbl-b. Semin Immunol 19(3):206–214. doi:10.1016/j.smim.2007.02.004

    Article  CAS  PubMed  Google Scholar 

  • Loeser S, Loser K, Bijker MS, Rangachari M, van der Burg SH, Wada T, Beissert S, Melief CJ, Penninger JM (2007) Spontaneous tumor rejection by cbl-b-deficient CD8 + T cells. J Exp Med 204(4):879–891. doi:10.1084/jem.20061699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu TT, Onizawa M, Hammer GE, Turer EE, Yin Q, Damko E, Agelidis A, Shifrin N, Advincula R, Barrera J, Malynn BA, Wu H, Ma A (2013) Dimerization and ubiquitin mediated recruitment of A20, a complex deubiquitinating enzyme. Immunity 38(5):896–905. doi:10.1016/j.immuni.2013.03.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lutz-Nicoladoni C, Wolf D, Sopper S (2015) Modulation of Immune Cell Functions by the E3 Ligase Cbl-b. Front Oncol 5:58. doi:10.3389/fonc.2015.00058

    Article  PubMed  PubMed Central  Google Scholar 

  • MacKenzie DA, Schartner J, Lin J, Timmel A, Jennens-Clough M, Fathman CG, Seroogy CM (2007) GRAIL is up-regulated in CD4 + CD25 + T regulatory cells and is sufficient for conversion of T cells to a regulatory phenotype. J Biol Chem 282(13):9696–9702. doi:10.1074/jbc.M604192200

    Article  CAS  PubMed  Google Scholar 

  • Marino A, Menghini R, Fabrizi M, Casagrande V, Mavilio M, Stoehr R, Candi E, Mauriello A, Moreno-Navarrete JM, Gomez-Serrano M, Peral B, Melino G, Lauro R, Fernandez Real JM, Federici M (2014) ITCH deficiency protects from diet-induced obesity. Diabetes 63(2):550–561. doi:10.2337/db13-0802

    Article  CAS  PubMed  Google Scholar 

  • Massoumi R, Chmielarska K, Hennecke K, Pfeifer A, Fassler R (2006) Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling. Cell 125(4):665–677. doi:10.1016/j.cell.2006.03.041

    Article  CAS  PubMed  Google Scholar 

  • Matmati M, Jacques P, Maelfait J, Verheugen E, Kool M, Sze M, Geboes L, Louagie E, Mc Guire C, Vereecke L, Chu Y, Boon L, Staelens S, Matthys P, Lambrecht BN, Schmidt-Supprian M, Pasparakis M, Elewaut D, Beyaert R, van Loo G (2011) A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis. Nat Genet 43(9):908–912. doi:10.1038/ng.874

    Article  CAS  PubMed  Google Scholar 

  • Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399(6733):271–275. doi:10.1038/20459

    Article  CAS  PubMed  Google Scholar 

  • Mc Guire C, Wieghofer P, Elton L, Muylaert D, Prinz M, Beyaert R, van Loo G (2013) Paracaspase MALT1 deficiency protects mice from autoimmune-mediated demyelination. J Immunol 190(6):2896–2903. doi:10.4049/jimmunol.1201351

    Article  CAS  PubMed  Google Scholar 

  • Murai M, Turovskaya O, Kim G, Madan R, Karp CL, Cheroutre H, Kronenberg M (2009) Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol 10(11):1178–1184. doi:10.1038/ni.1791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murakawa Y, Hinz M, Mothes J, Schuetz A, Uhl M, Wyler E, Yasuda T, Mastrobuoni G, Friedel CC, Dölken L (2015) RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-[kappa] B pathway. Nat Commun 6

    Google Scholar 

  • Muto G, Kotani H, Kondo T, Morita R, Tsuruta S, Kobayashi T, Luche H, Fehling HJ, Walsh M, Choi Y, Yoshimura A (2013) TRAF6 is essential for maintenance of regulatory T cells that suppress Th2 type autoimmunity. PLoS ONE 8(9):e74639. doi:10.1371/journal.pone.0074639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nagamachi A, Nakata Y, Ueda T, Yamasaki N, Ebihara Y, Tsuji K, Honda Z, Takubo K, Suda T, Oda H, Inaba T, Honda H (2014) Acquired deficiency of A20 results in rapid apoptosis, systemic inflammation, and abnormal hematopoietic stem cell function. PLoS ONE 9(1):e87425. doi:10.1371/journal.pone.0087425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Naito A, Azuma S, Tanaka S, Miyazaki T, Takaki S, Takatsu K, Nakao K, Nakamura K, Katsuki M, Yamamoto T, Inoue J (1999) Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells 4(6):353–362. doi:10.1046/j.1365-2443.1999.00265.x

  • Nakagawa MM, Thummar K, Mandelbaum J, Pasqualucci L, Rathinam CV (2015) Lack of the ubiquitin-editing enzyme A20 results in loss of hematopoietic stem cell quiescence. J Exp Med 212(2):203–216. doi:10.1084/jem.20132544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Naramura M, Jang IK, Kole H, Huang F, Haines D, Gu H (2002) c-Cbl and Cbl-b regulate T cell responsiveness by promoting ligand-induced TCR down-modulation. Nat Immunol 3(12):1192–1199. doi:10.1038/ni855

    Article  CAS  PubMed  Google Scholar 

  • Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK, Bernards R (2005) A genomic and functional inventory of deubiquitinating enzymes. Cell 123(5):773–786. doi:10.1016/j.cell.2005.11.007

    Article  CAS  PubMed  Google Scholar 

  • Nurieva RI, Zheng S, Jin W, Chung Y, Zhang Y, Martinez GJ, Reynolds JM, Wang SL, Lin X, Sun SC, Lozano G, Dong C (2010) The E3 ubiquitin ligase GRAIL regulates T cell tolerance and regulatory T cell function by mediating T cell receptor-CD3 degradation. Immunity 32(5):670–680. doi:10.1016/j.immuni.2010.05.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oliver PM, Cao X, Worthen GS, Shi P, Briones N, MacLeod M, White J, Kirby P, Kappler J, Marrack P, Yang B (2006) Ndfip1 protein promotes the function of itch ubiquitin ligase to prevent T cell activation and T helper 2 cell-mediated inflammation. Immunity 25(6):929–940. doi:10.1016/j.immuni.2006.10.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Onizawa M, Oshima S, Schulze-Topphoff U, Oses-Prieto JA, Lu T, Tavares R, Prodhomme T, Duong B, Whang MI, Advincula R (2015) The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis. Nat Immunol 16(6):618–627

    Article  CAS  Google Scholar 

  • Ou R, Zhang M, Huang L, Moskophidis D (2008) Control of virus-specific CD8 + T-cell exhaustion and immune-mediated pathology by E3 ubiquitin ligase Cbl-b during chronic viral infection. J Virol 82(7):3353–3368. doi:10.1128/JVI.01350-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paolino M, Thien CB, Gruber T, Hinterleitner R, Baier G, Langdon WY, Penninger JM (2011) Essential role of E3 ubiquitin ligase activity in Cbl-b-regulated T cell functions. J Immunol 186(4):2138–2147. doi:10.4049/jimmunol.1003390

    Article  CAS  PubMed  Google Scholar 

  • Park Y, Jin HS, Aki D, Lee J, Liu YC (2014) The ubiquitin system in immune regulation. Adv Immunol 124:17–66. doi:10.1016/B978-0-12-800147-9.00002-9

    Article  PubMed  Google Scholar 

  • Park Y, Jin HS, Lopez J, Lee J, Liao L, Elly C, Liu YC (2016) SHARPIN controls regulatory T cells by negatively modulating the T cell antigen receptor complex. Nat Immunol 17(3):286–296. doi:10.1038/ni.3352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pellegrini M, Calzascia T, Elford AR, Shahinian A, Lin AE, Dissanayake D, Dhanji S, Nguyen LT, Gronski MA, Morre M, Assouline B, Lahl K, Sparwasser T, Ohashi PS, Mak TW (2009) Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies. Nat Med 15(5):528–536. doi:10.1038/nm.1953

    Article  CAS  PubMed  Google Scholar 

  • Perry WL, Hustad CM, Swing DA, O’Sullivan TN, Jenkins NA, Copeland NG (1998) The itchy locus encodes a novel ubiquitin protein ligase that is disrupted in a(18H) mice. Nat Genet 18(2):143–146

    Article  CAS  Google Scholar 

  • Pujari R, Hunte R, Thomas R, van der Weyden L, Rauch D, Ratner L, Nyborg JK, Ramos JC, Takai Y, Shembade N (2015) Human T-cell leukemia virus type 1 (HTLV-1) tax requires CADM1/TSLC1 for inactivation of the NF-kappaB inhibitor A20 and constitutive NF-kappaB signaling. PLoS Pathog 11(3):e1004721. doi:10.1371/journal.ppat.1004721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qiao GL, Li ZP, Molinero L, Alegre ML, Ying HY, Sun ZM, Penninger JM, Zhang J (2008) T-Cell receptor-induced NF-kappa B activation is negatively regulated by E3 ubiquitin ligase Cbl-b. Mol Cell Biol 28(7):2470–2480

    Article  CAS  Google Scholar 

  • Qiao G, Ying H, Zhao Y, Liang Y, Guo H, Shen H, Li Z, Solway J, Tao E, Chiang YJ, Lipkowitz S, Penninger JM, Langdon WY, Zhang J (2014) E3 ubiquitin ligase Cbl-b suppresses proallergic T cell development and allergic airway inflammation. Cell Rep 6(4):709–723. doi:10.1016/j.celrep.2014.01.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ramon HE, Riling CR, Bradfield J, Yang B, Hakonarson H, Oliver PM (2011) The ubiquitin ligase adaptor Ndfip1 regulates T cell-mediated gastrointestinal inflammation and inflammatory bowel disease susceptibility. Mucosal Immunol 4(3):314–324. doi:10.1038/mi.2010.69

    Article  CAS  PubMed  Google Scholar 

  • Redecke V, Chaturvedi V, Kuriakose J, Hacker H (2016) SHARPIN controls the development of regulatory T cells. Immunology 148(2):216–226. doi:10.1111/imm.12604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reicher B, Joseph N, David A, Pauker MH, Perl O, Barda-Saad M (2012) Ubiquitylation-dependent negative regulation of WASp Is essential for actin cytoskeleton dynamics. Mol Cell Biol 32(15):3153–3163

    Article  CAS  Google Scholar 

  • Reiley WW, Zhang M, Jin W, Losiewicz M, Donohue KB, Norbury CC, Sun SC (2006) Regulation of T cell development by the deubiquitinating enzyme CYLD. Nat Immunol 7(4):411–417. doi:10.1038/ni1315

    Article  CAS  PubMed  Google Scholar 

  • Reiley WW, Jin W, Lee AJ, Wright A, Wu X, Tewalt EF, Leonard TO, Norbury CC, Fitzpatrick L, Zhang M, Sun SC (2007) Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. J Exp Med 204(6):1475–1485. doi:10.1084/jem.20062694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reissig S, Hovelmeyer N, Weigmann B, Nikolaev A, Kalt B, Wunderlich TF, Hahn M, Neurath MF, Waisman A (2012) The tumor suppressor CYLD controls the function of murine regulatory T cells. J Immunol 189(10):4770–4776. doi:10.4049/jimmunol.1201993

    Article  CAS  PubMed  Google Scholar 

  • Reissig S, Hovelmeyer N, Tang Y, Weih D, Nikolaev A, Riemann M, Weih F, Waisman A (2015) The deubiquitinating enzyme CYLD regulates the differentiation and maturation of thymic medullary epithelial cells. Immunol Cell Biol 93(6):558–566. doi:10.1038/icb.2014.122

    Article  CAS  PubMed  Google Scholar 

  • Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133(5):775–787. doi:10.1016/j.cell.2008.05.009

    Article  CAS  PubMed  Google Scholar 

  • Sarris M, Andersen KG, Randow F, Mayr L, Betz AG (2008) Neuropilin-1 expression on regulatory T cells enhances their interactions with dendritic cells during antigen recognition. Immunity 28(3):402–413. doi:10.1016/j.immuni.2008.01.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scharschmidt E, Wegener E, Heissmeyer V, Rao A, Krappmann D (2004) Degradation of Bcl10 induced by T-cell activation negatively regulates NF-kappa B signaling. Mol Cell Biol 24(9):3860–3873

    Article  CAS  Google Scholar 

  • Schuijs MJ, Willart MA, Vergote K, Gras D, Deswarte K, Ege MJ, Madeira FB, Beyaert R, van Loo G, Bracher F (2015) Farm dust and endotoxin protect against allergy through A20 induction in lung epithelial cells. Science 349(6252):1106–1110

    Article  CAS  Google Scholar 

  • Shamim M, Nanjappa SG, Singh A, Plisch EH, LeBlanc SE, Walent J, Svaren J, Seroogy C, Suresh M (2007) Cbl-b regulates antigen-induced TCR down-regulation and IFN-gamma production by effector CD8 T cells without affecting functional avidity. J Immunol 179(11):7233–7243

    Article  CAS  Google Scholar 

  • Shembade N, Harhaj NS, Parvatiyar K, Copeland NG, Jenkins NA, Matesic LE, Harhaj EW (2008) The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin-editing enzyme A20. Nat Immunol 9(3):254–262. doi:10.1038/ni1563

    Article  CAS  PubMed  Google Scholar 

  • Shembade N, Parvatiyar K, Harhaj NS, Harhaj EW (2009) The ubiquitin-editing enzyme A20 requires RNF11 to downregulate NF-kappaB signalling. EMBO J 28(5):513–522. doi:10.1038/emboj.2008.285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shembade N, Ma A, Harhaj EW (2010) Inhibition of NF-κB signaling by A20 through disruption of ubiquitin enzyme complexes. Science 327(5969):1135–1139

    Article  CAS  Google Scholar 

  • Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H (2011) HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208(7):1367–1376. doi:10.1084/jem.20110278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi ZD, Li XF, Hao L, Zhao Y, Wang YX, Dong BZ, Chen WH, Zhang ZG, Wang YM, Fu Q, Han CH, Li S (2014) Cbl-b gene silencing in splenic T lymphocytes as a therapeutic strategy to target the prostate cancer RM-1 cell tumors in immune competent mice. Eur Rev Med Pharmacol Sci 18(24):3819–3830

    PubMed  Google Scholar 

  • Shimo Y, Yanai H, Ohshima D, Qin J, Motegi H, Maruyama Y, Hori S, Inoue J, Akiyama T (2011) TRAF6 directs commitment to regulatory T cells in thymocytes. Genes Cells 16(4):437–447. doi:10.1111/j.1365-2443.2011.01500.x

    Article  CAS  PubMed  Google Scholar 

  • Song HY, Rothe M, Goeddel DV (1996) The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation. Proc Natl Acad Sci USA 93(13):6721–6725

    Article  CAS  Google Scholar 

  • Song X-T, Kabler KE, Shen L, Rollins L, Huang XF, Chen S-Y (2008) A20 is an antigen presentation attenuator, and its inhibition overcomes regulatory T cell–mediated suppression. Nat Med 14(3):258–265

    Article  CAS  Google Scholar 

  • Soyer OU, Akdis M, Ring J, Behrendt H, Crameri R, Lauener R, Akdis CA (2013) Mechanisms of peripheral tolerance to allergens. Allergy 68(2):161–170. doi:10.1111/all.12085

    Article  CAS  PubMed  Google Scholar 

  • St Rose MC, Qui HZ, Bandyopadhyay S, Mihalyo MA, Hagymasi AT, Clark RB, Adler AJ (2009) The E3 ubiquitin ligase Cbl-b regulates expansion but not functional activity of self-reactive CD4 T cells. J Immunol 183(8):4975–4983

    Article  CAS  Google Scholar 

  • Stone EL, Pepper M, Katayama CD, Kerdiles YM, Lai CY, Emslie E, Lin YC, Yang E, Goldrath AW, Li MO, Cantrell DA, Hedrick SM (2015) ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. Immunity 42(2):239–251. doi:10.1016/j.immuni.2015.01.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stromnes IM, Blattman JN, Tan X, Jeevanjee S, Gu H, Greenberg PD (2010) Abrogating Cbl-b in effector CD8(+) T cells improves the efficacy of adoptive therapy of leukemia in mice. J Clin Invest 120(10):3722–3734. doi:10.1172/JCI41991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun SC (2008) Deubiquitylation and regulation of the immune response. Nat Rev Immunol 8(7):501–511. doi:10.1038/nri2337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tavares RM, Turer EE, Liu CL, Advincula R, Scapini P, Rhee L, Barrera J, Lowell CA, Utz PJ, Malynn BA, Ma A (2010) The ubiquitin modifying enzyme A20 restricts B cell survival and prevents autoimmunity. Immunity 33(2):181–191. doi:10.1016/j.immuni.2010.07.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Teh CE, Lalaoui N, Jain R, Policheni AN, Heinlein M, Alvarez-Diaz S, Sheridan JM, Rieser E, Deuser S, Darding M, Koay HF, Hu Y, Kupresanin F, O’Reilly LA, Godfrey DI, Smyth GK, Bouillet P, Strasser A, Walczak H, Silke J, Gray DH (2016) Linear ubiquitin chain assembly complex coordinates late thymic T-cell differentiation and regulatory T-cell homeostasis. Nat Commun 7:13353. doi:10.1038/ncomms13353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tiruppathi C, Soni D, Wang DM, Xue J, Singh V, Thippegowda PB, Cheppudira BP, Mishra RK, Debroy A, Qian Z, Bachmaier K, Zhao YY, Christman JW, Vogel SM, Ma A, Malik AB (2014) The transcription factor DREAM represses the deubiquitinase A20 and mediates inflammation. Nat Immunol 15(3):239–247. doi:10.1038/ni.2823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsagaratou A, Trompouki E, Grammenoudi S, Kontoyiannis DL, Mosialos G (2010) Thymocyte-specific truncation of the deubiquitinating domain of CYLD impairs positive selection in a NF-kappaB essential modulator-dependent manner. J Immunol 185(4):2032–2043. doi:10.4049/jimmunol.0903919

    Article  CAS  PubMed  Google Scholar 

  • Turer EE, Tavares RM, Mortier E, Hitotsumatsu O, Advincula R, Lee B, Shifrin N, Malynn BA, Ma A (2008) Homeostatic MyD88-dependent signals cause lethal inflamMation in the absence of A20. J Exp Med 205(2):451–464. doi:10.1084/jem.20071108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Venuprasad K, Elly C, Gao M, Salek-Ardakani S, Harada Y, Luo JL, Yang C, Croft M, Inoue K, Karin M, Liu YC (2006) Convergence of Itch-induced ubiquitination with MEKK1-JNK signaling in Th2 tolerance and airway inflammation. J Clin Invest 116(4):1117–1126. doi:10.1172/JCI26858

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Venuprasad K, Huang H, Harada Y, Elly C, Subramaniam M, Spelsberg T, Su J, Liu YC (2008) The E3 ubiquitin ligase Itch regulates expression of transcription factor Foxp3 and airway inflammation by enhancing the function of transcription factor TIEG1. Nat Immunol 9(3):245–253. doi:10.1038/ni1564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vereecke L, Vieira-Silva S, Billiet T, van Es JH, Mc Guire C, Slowicka K, Sze M, van den Born M, De Hertogh G, Clevers H (2014) A20 controls intestinal homeostasis through cell-specific activities. Nat Commun 5

    Google Scholar 

  • Verhelst K, Carpentier I, Kreike M, Meloni L, Verstrepen L, Kensche T, Dikic I, Beyaert R (2012) A20 inhibits LUBAC-mediated NF-kappaB activation by binding linear polyubiquitin chains via its zinc finger 7. EMBO J 31(19):3845–3855. doi:10.1038/emboj.2012.240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Walker LS, Abbas AK (2002) The enemy within: keeping self-reactive T cells at bay in the periphery. Nat Rev Immunol 2(1):11–19. doi:10.1038/nri701

    Article  CAS  PubMed  Google Scholar 

  • Walsh MC, Lee J, Choi Y (2015) Tumor necrosis factor receptor- associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system. Immunol Rev 266(1):72–92. doi:10.1111/imr.12302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang J, Ouyang Y, Guner Y, Ford HR, Grishin AV (2009) Ubiquitin-editing enzyme A20 promotes tolerance to lipopolysaccharide in enterocytes. J Immunol 183(2):1384–1392. doi:10.4049/jimmunol.0803987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang L, Hong B, Jiang X, Jones L, Chen SY, Huang XF (2012) A20 controls macrophage to elicit potent cytotoxic CD4(+) T cell response. PLoS ONE 7(11):e48930. doi:10.1371/journal.pone.0048930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang X, Deckert M, Xuan NT, Nishanth G, Just S, Waisman A, Naumann M, Schluter D (2013) Astrocytic A20 ameliorates experimental autoimmune encephalomyelitis by inhibiting NF-kappaB- and STAT1-dependent chemokine production in astrocytes. Acta Neuropathol 126(5):711–724. doi:10.1007/s00401-013-1183-9

    Article  CAS  PubMed  Google Scholar 

  • Watanabe Y, Sasahara Y, Ramesh N, Massaad MJ, Yeng Looi C, Kumaki S, Kure S, Geha RS, Tsuchiya S (2013) T-cell receptor ligation causes Wiskott-Aldrich syndrome protein degradation and F-actin assembly downregulation. J Allergy Clin Immunol 132(3):648–655 e641. doi:10.1016/j.jaci.2013.03.046

  • Wertz IE, O’Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S, Wu P, Wiesmann C, Baker R, Boone DL, Ma A, Koonin EV, Dixit VM (2004) De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature 430(7000):694–699. doi:10.1038/nature02794

    Article  CAS  PubMed  Google Scholar 

  • Wertz IE, Newton K, Seshasayee D, Kusam S, Lam C, Zhang J, Popovych N, Helgason E, Schoeffler A, Jeet S, Ramamoorthi N, Kategaya L, Newman RJ, Horikawa K, Dugger D, Sandoval W, Mukund S, Zindal A, Martin F, Quan C, Tom J, Fairbrother WJ, Townsend M, Warming S, DeVoss J, Liu J, Dueber E, Caplazi P, Lee WP, Goodnow CC, Balazs M, Yu K, Kolumam G, Dixit VM (2015) Phosphorylation and linear ubiquitin direct A20 inhibition of inflammation. Nature 528(7582):370–375. doi:10.1038/nature16165

    Article  CAS  PubMed  Google Scholar 

  • Wex K, Schmid U, Just S, Wang X, Wurm R, Naumann M, Schluter D, Nishanth G (2015) Receptor-interacting protein Kinase-2 inhibition by CYLD impairs antibacterial immune responses in macrophages. Front Immunol 6:650. doi:10.3389/fimmu.2015.00650

    Article  CAS  PubMed  Google Scholar 

  • Wiedemann A, Muller S, Favier B, Penna D, Guiraud M, Delmas C, Champagne E, Valitutti S (2005) T-cell activation is accompanied by an ubiquitination process occurring at the immunological synapse. Immunol Lett 98(1):57–61

    Article  CAS  Google Scholar 

  • Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S (2008) CTLA-4 control over Foxp3 + regulatory T cell function. Science 322(5899):271–275. doi:10.1126/science.1160062

    Article  CAS  Google Scholar 

  • Wohlfert EA, Callahan MK, Clark RB (2004) Resistance to CD4(+)CD25(+) regulatory T cells and TGF-beta in Cbl-b(-/-) mice. J Immunol 173(2):1059–1065

    Article  CAS  Google Scholar 

  • Wohlfert EA, Gorelik L, Mittler R, Flavell RA, Clark RB (2006) Cutting edge: deficiency in the E3 ubiquitin ligase Cbl-b results in a multifunctional defect in T cell TGF-beta sensitivity in vitro and in vivo. J Immunol 176(3):1316–1320

    Article  CAS  Google Scholar 

  • Xiao NM, Eto D, Elly C, Peng GY, Crotty S, Liu YC (2014) The E3 ubiquitin ligase Itch is required for the differentiation of follicular helper T cells. Nat Immunol 15(7):657–666

    Article  CAS  Google Scholar 

  • Xiao Y, Qiao G, Tang J, Tang R, Guo H, Warwar S, Langdon WY, Tao L, Zhang J (2015) Protein tyrosine phosphatase SHP-1 modulates T cell responses by controlling Cbl-b degradation. J Immunol 195(9):4218–4227. doi:10.4049/jimmunol.1501200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamaguchi N, Oyama M, Kozuka-Hata H, Inoue J-i (2013) Involvement of A20 in the molecular switch that activates the non-canonical NF-кB pathway. Scientific Reports 3

    Google Scholar 

  • Yang C, Zhou W, Jeon MS, Demydenko D, Harada Y, Zhou H, Liu YC (2006) Negative regulation of the E3 ubiquitin ligase itch via Fyn-mediated tyrosine phosphorylation. Mol Cell 21(1):135–141. doi:10.1016/j.molcel.2005.11.014

    Article  CAS  PubMed  Google Scholar 

  • Yang B, Gay DL, MacLeod MK, Cao X, Hala T, Sweezer EM, Kappler J, Marrack P, Oliver PM (2008) Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells. Nat Immunol 9(12):1356–1363. doi:10.1038/ni.1670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang TM, Martin ML, Nielsen JS, Milne K, Wall EM, Lin W, Watson PH, Nelson BH (2009) Mammary tumors with diverse immunological phenotypes show differing sensitivity to adoptively transferred CD8 + T cells lacking the Cbl-b gene. Cancer Immunol Immunother 58(11):1867–1877

    Article  Google Scholar 

  • Yin S, Zhang J, Mao Y, Hu Y, Cui L, Kang N, He W (2013) Vav1-phospholipase C-gamma1 (Vav1-PLC-gamma1) pathway initiated by T cell antigen receptor (TCRgammadelta) activation is required to overcome inhibition by ubiquitin ligase Cbl-b during gammadeltaT cell cytotoxicity. J Biol Chem 288(37):26448–26462. doi:10.1074/jbc.M113.484600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yuk JM, Kim TS, Kim SY, Lee HM, Han J, Dufour CR, Kim JK, Jin HS, Yang CS, Park KS, Lee CH, Kim JM, Kweon GR, Choi HS, Vanacker JM, Moore DD, Giguere V, Jo EK (2015) Orphan nuclear receptor ERRalpha controls macrophage metabolic signaling and A20 expression to negatively regulate TLR-induced inflammation. Immunity 43(1):80–91. doi:10.1016/j.immuni.2015.07.003

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Bardos T, Li DD, Gal I, Vermes C, Xu JY, Mikecz K, Finnegan A, Lipkowitz S, Glant TT (2002) Cutting edge: Regulation of T cell activation threshold by CD28 costimulation through targeting Cbl-b for ubiquitination. J Immunol 169(5):2236–2240

    Article  CAS  Google Scholar 

  • Zhang W, Shao Y, Fang D, Huang J, Jeon MS, Liu YC (2003) Negative regulation of T cell antigen receptor-mediated Crk-L-C3G signaling and cell adhesion by Cbl-b. J Biol Chem 278(26):23978–23983. doi:10.1074/jbc.M212671200

    Article  CAS  PubMed  Google Scholar 

  • Zhang J, Stirling B, Temmerman ST, Ma CA, Fuss IJ, Derry JM, Jain A (2006) Impaired regulation of NF-kappaB and increased susceptibility to colitis-associated tumorigenesis in CYLD-deficient mice. J Clin Invest 116(11):3042–3049. doi:10.1172/JCI28746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang R, Zhang N, Mueller DL (2008) Casitas B-lineage lymphoma b inhibits antigen recognition and slows cell cycle progression at late times during CD4 + T cell clonal expansion. J Immunol 181(8):5331–5339

    Article  CAS  Google Scholar 

  • Zhao Y, Guo H, Qiao G, Zucker M, Langdon WY, Zhang J (2015) E3 ubiquitin ligase Cbl-b regulates thymic-derived CD4 + CD25 + regulatory T cell development by targeting Foxp3 for ubiquitination. J Immunol 194(4):1639–1645. doi:10.4049/jimmunol.1402434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao Y, Thornton AM, Kinney MC, Ma CA, Spinner JJ, Fuss IJ, Shevach EM, Jain A (2011) The deubiquitinase CYLD targets Smad7 protein to regulate transforming growth factor beta (TGF-beta) signaling and the development of regulatory T cells. J Biol Chem 286(47):40520–40530. doi:10.1074/jbc.M111.292961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng Y, Zha Y, Gajewski TF (2008) Molecular regulation of T-cell anergy. EMBO Rep 9(1):50–55. doi:10.1038/sj.embor.7401138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou SK, Chen WH, Shi ZD, Wang SP, Li L, Wen XF, Wang YM (2014) Silencing the expression of Cbl-b enhances the immune activation of T lymphocytes against RM-1 prostate cancer cells in vitro. J Chin Med Assoc 77(12):630–636. doi:10.1016/j.jcma.2014.03.008

    Article  PubMed  Google Scholar 

  • Zhou Q, Wang H, Schwartz DM, Stoffels M, Park YH, Zhang Y, Yang D, Demirkaya E, Takeuchi M, Tsai WL, Lyons JJ, Yu X, Ouyang C, Chen C, Chin DT, Zaal K, Chandrasekharappa SC, E PH, Yu Z, Mullikin JC, Hasni SA, Wertz IE, Ombrello AK, Stone DL, Hoffmann P, Jones A, Barham BK, Leavis HL, van Royen-Kerkof A, Sibley C, Batu ED, Gul A, Siegel RM, Boehm M, Milner JD, Ozen S, Gadina M, Chae J, Laxer RM, Kastner DL, Aksentijevich I (2016) Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat Genet 48(1):67–73. doi:10.1038/ng.3459

  • Zilberman-Rudenko J, Shawver LM, Wessel AW, Luo Y, Pelletier M, Tsai WL, Lee Y, Vonortas S, Cheng L, Ashwell JD, Orange JS, Siegel RM, Hanson EP (2016) Recruitment of A20 by the C-terminal domain of NEMO suppresses NF-kappaB activation and autoinflammatory disease. Proc Natl Acad Sci USA 113(6):1612–1617. doi:10.1073/pnas.1518163113

    Article  CAS  PubMed  Google Scholar 

  • Zou W (2006) Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 6(4):295–307. doi:10.1038/nri1806

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work is supported by funding from Tsinghua-Peking center of life sciences, NSFC 81630041,MOST YFC0903900, NIH RO1AI123398, and R21AI122258.

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Authors and Affiliations

  1. Institute for Immunology, Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, 100084, China

    Peng Zeng, Jieyu Ma, Runqing Yang & Yun-Cai Liu

  2. Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92037, USA

    Yun-Cai Liu

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  1. Peng Zeng
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  2. Jieyu Ma
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  3. Runqing Yang
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Correspondence to Yun-Cai Liu .

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  1. Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan

    Akihiko Yoshimura

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Zeng, P., Ma, J., Yang, R., Liu, YC. (2017). Immune Regulation by Ubiquitin Tagging as Checkpoint Code. In: Yoshimura, A. (eds) Emerging Concepts Targeting Immune Checkpoints in Cancer and Autoimmunity. Current Topics in Microbiology and Immunology, vol 410. Springer, Cham. https://doi.org/10.1007/82_2017_64

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