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Intracellular Antibody Immunity and the Cytosolic Fc Receptor TRIM21

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Fc Receptors

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 382))

Abstract

Until recently, it was thought that antibody effector mechanisms were mediated purely by Fc receptors expressed on professional cells, following capture of immune complexes in the extracellular space. Recently a new Fc receptor, TRIM21, was discovered that is expressed by cells of all histogenetic lineages and which mediates immune responses intracellularly. This new receptor possesses many unique structural and functional properties. TRIM21 binds both IgG and IgM, interacts primarily with the CH3 rather than CH2 domain and engages two heavy chains simultaneously. This latter property allows TRIM21 to bind antibodies with a higher affinity than any other Fc receptor. TRIM21 is cytosolic, has both effector and signalling functions and is exquisitely conserved in mammals. The discovery of this missing part of humoral immunity has important implications for where and how antibodies work.

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References

  • Ben-Chetrit E, Chan EK et al (1988) A 52-kD protein is a novel component of the SS-A/Ro antigenic particle. J Exp Med 167(5):1560–1571

    Article  PubMed  CAS  Google Scholar 

  • Ben-Chetrit E, Fox RI et al (1990) Dissociation of immune responses to the SS-A (Ro) 52-kd and 60-kd polypeptides in systemic lupus erythematosus and Sjogren’s syndrome. Arthritis Rheum 33(3):349–355

    Article  PubMed  CAS  Google Scholar 

  • Beskow A, Grimberg KB et al (2009) A conserved unfoldase activity for the p97 AAA-ATPase in proteasomal degradation. J Mol Biol 394(4):732–746

    Article  PubMed  CAS  Google Scholar 

  • Biris N, Yang Y et al (2012) Structure of the rhesus monkey TRIM5alpha PRYSPRY domain, the HIV capsid recognition module. Proc Natl Acad Sci USA 109(33):13278–13283

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • D’Cruz AA, Kershaw NJ et al (2013) Crystal structure of the TRIM25 B30.2 (PRYSPRY) domain: a key component of antiviral signalling. Biochem J 456(2):231–240

    Article  PubMed  Google Scholar 

  • Diaz-Griffero F, Qin XR et al (2009) A B-box 2 surface patch important for TRIM5alpha self-association, capsid binding avidity, and retrovirus restriction. J Virol 83(20):10737–10751

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Espinosa A, Dardalhon V et al (2009) Loss of the lupus autoantigen Ro52/TRIM21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23-Th17 pathway. J Exp Med 206(8):1661–1671

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Frank MB, Itoh K et al (1993) The mapping of the human 52-kD Ro/SSA autoantigen gene to human chromosome 11, and its polymorphisms. Am J Hum Genet 52(1):183–191

    PubMed  CAS  PubMed Central  Google Scholar 

  • Gallivan JP, Dougherty DA (1999) Cation-pi interactions in structural biology. Proc Natl Acad Sci USA 96(17):9459–9464

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Gassama-Diagne A, Hullin-Matsuda F et al (2001) Enterophilins, a new family of leucine zipper proteins bearing a b30.2 domain and associated with enterocyte differentiation. J Biol Chem 276(21):18352–18360

    Article  PubMed  CAS  Google Scholar 

  • Ghadessy FJ, Jeyaseelan K et al (1994) A genomic region encoding stonefish (Synanceja horrida) stonustoxin beta-subunit contains an intron. Toxicon 32(12):1684–1688

    Article  PubMed  CAS  Google Scholar 

  • Hauler F, Mallery DL et al (2012) AAA ATPase p97/VCP is essential for TRIM21-mediated virus neutralization. Proc Natl Acad Sci USA 109(48):19733–19738

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Higgs R, Ni Gabhann J et al (2008) The E3 ubiquitin ligase Ro52 negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. J Immunol 181(3):1780–1786

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Horn EJ, Albor A et al (2004) RING protein Trim32 associated with skin carcinogenesis has anti-apoptotic and E3-ubiquitin ligase properties. Carcinogenesis 25(2):157–167

    Article  PubMed  CAS  Google Scholar 

  • Isakov E, Stanhill A (2011) Stalled proteasomes are directly relieved by P97 recruitment. J Biol Chem 286(35):30274–30283

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • James LC, Keeble AH et al (2007) Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function. Proc Natl Acad Sci USA 104(15):6200–6205

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Keeble AH, Khan Z et al (2008) TRIM21 is an IgG receptor that is structurally, thermodynamically, and kinetically conserved. Proc Natl Acad Sci USA 105(16):6045–6050

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kong HJ, Anderson DE et al (2007) Cutting edge: autoantigen Ro52 is an interferon inducible E3 ligase that ubiquitinates IRF-8 and enhances cytokine expression in macrophages. J Immunol 179(1):26–30

    Article  PubMed  CAS  Google Scholar 

  • Kudryashova E, Kudryashov D et al (2005) Trim32 is a ubiquitin ligase mutated in limb girdle muscular dystrophy type 2H that binds to skeletal muscle myosin and ubiquitinates actin. J Mol Biol 354(2):413–424

    Article  PubMed  CAS  Google Scholar 

  • Landau M, Mayrose I et al (2005) ConSurf 2005: the projection of evolutionary conservation scores of residues on protein structures. Nucleic Acids Res 33(Web Server issue):W299–W302

    Google Scholar 

  • Letunic I, Copley RR et al (2006) SMART 5: domains in the context of genomes and networks. Nucleic Acids Res 34(Database issue):D257–D260

    Google Scholar 

  • Mallery DL, McEwan WA et al (2010) Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21). Proc Natl Acad Sci USA 107(46):19985–19990

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Masters SL, Yao S et al (2006) The SPRY domain of SSB-2 adopts a novel fold that presents conserved Par-4-binding residues. Nat Struct Mol Biol 13(1):77–84

    Article  PubMed  CAS  Google Scholar 

  • McCauliffe DP, Wang L et al (1997) Recombinant 52 kDa Ro(SSA) ELISA detects autoantibodies in Sjogren’s syndrome sera that go undetected by conventional serologic assays. J Rheumatol 24(5):860–866

    PubMed  CAS  Google Scholar 

  • McEwan WA, Hauler F et al (2012) Regulation of virus neutralization and the persistent fraction by TRIM21. J Virol 86(16):8482–8491

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • McEwan WA, Tam JC et al (2013) Intracellular antibody-bound pathogens stimulate immune signaling via the Fc receptor TRIM21. Nat Immunol 14(4):327–336

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Moutsopoulos HM, Skopouli FN et al (1985) Anti-Ro(SSA) positive rheumatoid arthritis (RA): a clinicoserological group of patients with high incidence of D-penicillamine side effects. Ann Rheum Dis 44(4):215–219

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Pung YF, Wong PT et al (2005) Ohanin, a novel protein from king cobra venom, induces hypolocomotion and hyperalgesia in mice. J Biol Chem 280(13):13137–13147

    Article  PubMed  CAS  Google Scholar 

  • Randow F, MacMicking JD et al (2013) Cellular self-defense: how cell-autonomous immunity protects against pathogens. Science 340(6133):701–706

    Article  PubMed  CAS  Google Scholar 

  • Rhodes DA, de Bono B et al (2005) Relationship between SPRY and B30.2 protein domains. Evolution of a component of immune defence? Immunology 116(4):411–417

    PubMed  CAS  PubMed Central  Google Scholar 

  • Rhodes DA, Ihrke G et al (2002) The 52 000 MW Ro/SS-A autoantigen in Sjogren’s syndrome/systemic lupus erythematosus (Ro52) is an interferon-gamma inducible tripartite motif protein associated with membrane proximal structures. Immunology 106(2):246–256

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Sabile A, Meyer AM et al (2006) Regulation of p27 degradation and S-phase progression by Ro52 RING finger protein. Mol Cell Biol 26(16):5994–6004

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Salomonsson S, Sonesson SE et al (2005) Ro/SSA autoantibodies directly bind cardiomyocytes, disturb calcium homeostasis, and mediate congenital heart block. J Exp Med 201(1):11–17

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Short KM, Cox TC (2006) Subclassification of the RBCC/TRIM superfamily reveals a novel motif necessary for microtubule binding. J Biol Chem 281(13):8970–8980

    Article  PubMed  CAS  Google Scholar 

  • Tanaka M, Kamitani T (2010) Cytoplasmic relocation of Daxx induced by Ro52 and FLASH. Histochem Cell Biol 134(3):297–306

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Trockenbacher A, Suckow V et al (2001) MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation. Nat Genet 29(3):287–294

    Article  PubMed  CAS  Google Scholar 

  • Urano T, Saito T et al (2002) Efp targets 14-3-3 sigma for proteolysis and promotes breast tumour growth. Nature 417(6891):871–875

    Article  PubMed  CAS  Google Scholar 

  • Vaysburd M, Watkinson RE et al (2013) Intracellular antibody receptor TRIM21 prevents fatal viral infection. Proc Natl Acad Sci USA 110(30):12397–12401

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Vichi A, Payne DM et al (2005) E3 ubiquitin ligase activity of the trifunctional ARD1 (ADP-ribosylation factor domain protein 1). Proc Natl Acad Sci USA 102(6):1945–1950

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Wada K, Niida M et al (2009) Ro52-mediated monoubiquitination of IKK{beta} down-regulates NF-{kappa}B signalling. J Biochem 146(6):821–832

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Watkinson RE, Tam JC et al (2013) Simultaneous neutralization and innate immune detection of a replicating virus by TRIM21. J Virol 87(13):7309–7313

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Weinert C, Grutter C et al (2009) The crystal structure of human pyrin b30.2 domain: implications for mutations associated with familial Mediterranean fever. J Mol Biol 394(2):226–236

    Article  PubMed  CAS  Google Scholar 

  • Woo JS, Imm JH et al (2006) Structural and functional insights into the B30.2/SPRY domain. EMBO J 25(6):1353–1363

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Xu L, Yang L et al (2003) BTBD1 and BTBD2 colocalize to cytoplasmic bodies with the RBCC/tripartite motif protein, TRIM5delta. Exp Cell Res 288(1):84–93

    Article  PubMed  CAS  Google Scholar 

  • Yang K, Shi HX et al (2009) TRIM21 is essential to sustain IFN regulatory factor 3 activation during antiviral response. J Immunol 182(6):3782–3792

    Article  PubMed  CAS  Google Scholar 

  • Yang Y, Eversole T et al (1999) Protein-protein interactions between native Ro52 and immunoglobulin G heavy chain. Scand J Immunol 49(6):620–628

    Article  PubMed  CAS  Google Scholar 

  • Yang YS, Yang MC et al (2000) Autoantigen Ro52 directly interacts with human IgG heavy chain in vivo in mammalian cells. Mol Immunol 37(10):591–602

    Article  PubMed  CAS  Google Scholar 

  • Yergeau DA, Cornell CN et al (2005) Bloodthirsty, an RBCC/TRIM gene required for erythropoiesis in zebrafish. Dev Biol 283(1):97–112

    Article  PubMed  CAS  Google Scholar 

  • Young JA, Sermwittayawong D et al (2011) Fas-associated death domain (FADD) and the E3 ubiquitin-protein ligase TRIM21 interact to negatively regulate virus-induced interferon production. J Biol Chem 286(8):6521–6531

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Zhang Z, Bao M et al (2013) The E3 ubiquitin ligase TRIM21 negatively regulates the innate immune response to intracellular double-stranded DNA. Nat Immunol 14(2):172–178

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. MRC Laboratory of Molecular Biology, Cambridge, UK

    Leo C. James

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  1. Leo C. James
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Correspondence to Leo C. James .

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Editors and Affiliations

  1. Institut Pasteur, Paris, France

    Marc Daeron

  2. Department of Biology, Institute of Genetics, University of Erlangen-Nürnberg, Erlangen, Germany

    Falk Nimmerjahn

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James, L.C. (2014). Intracellular Antibody Immunity and the Cytosolic Fc Receptor TRIM21. In: Daeron, M., Nimmerjahn, F. (eds) Fc Receptors. Current Topics in Microbiology and Immunology, vol 382. Springer, Cham. https://doi.org/10.1007/978-3-319-07911-0_3

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