Deubiquitinases as pivotal regulators of T cell functions

Xiao-Dong Yang , Shao-Cong Sun

Front. Med. ›› 2018, Vol. 12 ›› Issue (4) : 451 -462.

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Front. Med. ›› 2018, Vol. 12 ›› Issue (4) : 451 -462. DOI: 10.1007/s11684-018-0651-y
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Deubiquitinases as pivotal regulators of T cell functions

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Abstract

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.

Keywords

deubiquitinase / ubiquitination / T cell activation / T cell differentiation / T cell tolerance

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Xiao-Dong Yang, Shao-Cong Sun. Deubiquitinases as pivotal regulators of T cell functions. Front. Med., 2018, 12(4): 451-462 DOI:10.1007/s11684-018-0651-y

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References

[1]

Smith-Garvin JE, Koretzky GA, Jordan MS. T cell activation. Annu Rev Immunol 2009; 27(1): 591–619

[2]

Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations. Annu Rev Immunol 2010; 28(1): 445–489

[3]

Goodnow CC, Sprent J, Fazekas de St Groth B, Vinuesa CG. Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature 2005; 435(7042): 590–597

[4]

Xing Y, Hogquist KA. T-cell tolerance: central and peripheral. Cold Spring Harb Perspect Biol 2012; 4(6): a006957

[5]

O’Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 2010; 327(5969): 1098–1102

[6]

Crotty S. T follicular helper cell differentiation, function, and roles in disease. Immunity 2014; 41(4): 529–542

[7]

Damsker JM, Hansen AM, Caspi RR. Th1 and Th17 cells: adversaries and collaborators. Ann N Y Acad Sci 2010; 1183(1): 211–221

[8]

Zhang N, Bevan MJ. CD8+ T cells: foot soldiers of the immune system. Immunity 2011; 35(2): 161–168

[9]

Halle S, Halle O, Förster R. Mechanisms and dynamics of T cell-mediated cytotoxicity in vivo. Trends Immunol 2017; 38(6): 432–443

[10]

Steinman RM. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 1991; 9(1): 271–296

[11]

Kennedy R, Celis E. Multiple roles for CD4+ T cells in anti-tumor immune responses. Immunol Rev 2008; 222(1): 129–144

[12]

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

[13]

Ohashi PS. T-cell signalling and autoimmunity: molecular mechanisms of disease. Nat Rev Immunol 2002; 2(6): 427–438

[14]

Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem 1998; 67(1): 425–479

[15]

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

[16]

Akutsu M, Dikic I, Bremm A. Ubiquitin chain diversity at a glance. J Cell Sci 2016; 129(5): 875–880

[17]

Ikeda F. Linear ubiquitination signals in adaptive immune responses. Immunol Rev 2015; 266(1): 222–236

[18]

Chen J, Chen ZJ. Regulation of NF-kB by ubiquitination. Curr Opin Immunol 2013; 25(1): 4–12

[19]

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

[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

[21]

Mevissen TET, Komander D. Mechanisms of deubiquitinase specificity and regulation. Annu Rev Biochem 2017; 86(1): 159–192

[22]

Germain RN. T-cell development and the CD4-CD8 lineage decision. Nat Rev Immunol 2002; 2(5): 309–322

[23]

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

[24]

Hu H, Sun SC. Ubiquitin signaling in immune responses. Cell Res 2016; 26(4): 457–483

[25]

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

[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

[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

[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

[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

[30]

Bendelac A, Savage PB, Teyton L. The biology of NKT cells. Annu Rev Immunol 2007; 25(1): 297–336

[31]

Crosby CM, Kronenberg M. Invariant natural killer T cells: front line fighters in the war against pathogenic microbes. Immunogenetics 2016; 68(8): 639–648

[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 CD4CD8 thymocytes that bypasses the CD4+CD8+ stage. Nat Immunol 2017; 18(3): 274–282

[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

[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

[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

[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

[37]

Chen ZJ. Ubiquitination in signaling to and activation of IKK. Immunol Rev 2012; 246(1): 95–106

[38]

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

[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

[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

[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

[42]

Harhaj EW, Dixit VM. Deubiquitinases in the regulation of NF-kB signaling. Cell Res 2011; 21(1): 22–39

[43]

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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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): 12–23PMID:23405892

[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

[58]

Walsh KP, Mills KH. Dendritic cells and other innate determinants of T helper cell polarisation. Trends Immunol 2013; 34(11): 521–530

[59]

Berenson LS, Ota N, Murphy KM. Issues in T-helper 1 development—resolved and unresolved. Immunol Rev 2004; 202(1): 157–174

[60]

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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[72]

Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell 2008; 133(5): 775–787

[73]

Lee AJ, Wu X, Cheng H, Zhou X, Cheng X, Sun SC. CARMA1 regulation of regulatory T cell development involves modulation of interleukin-2 receptor signaling. J Biol Chem 2010; 285(21): 15696–15703

[74]

Oh H, Ghosh S. NF-kB: roles and regulation in different CD4+ T-cell subsets. Immunol Rev 2013; 252(1): 41–51

[75]

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

[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

[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

[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

[79]

van Loosdregt J, Coffer PJ. Post-translational modification networks regulating FOXP3 function. Trends Immunol 2014; 35(8): 368–378

[80]

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

[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

[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

[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

[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

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