TRIM35 mediates protection against influenza infection by activating TRAF3 and degrading viral PB2

Abstract

Tripartite motif (TRIM) family proteins are important effectors of innate immunity against viral infections. Here we identified TRIM35 as a regulator of TRAF3 activation. Deficiency in or inhibition of TRIM35 suppressed the production of type I interferon (IFN) in response to viral infection. Trim35-deficient mice were more susceptible to influenza A virus (IAV) infection than were wild-type mice. TRIM35 promoted the RIG-Imediated signaling by catalyzing Lys63-linked polyubiquitination of TRAF3 and the subsequent formation of a signaling complex with VISA and TBK1. IAV PB2 polymerase countered the innate antiviral immune response by impeding the Lys63-linked polyubiquitination and activation of TRAF3. TRIM35 mediated Lys48-linked polyubiquitination and proteasomal degradation of IAV PB2, thereby antagonizing its suppression of TRAF3 activation. Our in vitro and in vivo findings thus reveal novel roles of TRIM35, through catalyzing Lys63-or Lys48-linked polyubiquitination, in RIG-I antiviral immunity and mechanism of defense against IAV infection.

Keywords

influenza A virus / PB2 / TRIM35 / TRAF3 / ubiquitination / antiviral immunity

References

[1] Arranz R, Coloma R, Chichon FJ, Conesa JJ, Carrascosa JL, Valpuesta JM, Ortin J, Martin-Benito J (2012) The structure of native influenza virion ribonucleoproteins. Science 338:1634–1637

[2] Baum A, Sachidanandam R, Garcia-Sastre A (2010) Preference of RIG-I for short viral RNA molecules in infected cells revealed by next-generation sequencing. Proc Natl Acad Sci USA 107:16303–16308

[3] Chen Z, Wang Z, Guo W, Zhang Z, Zhao F, Zhao Y, Jia D, Ding J, Wang H, Yao M (2015) TRIM35 Interacts with pyruvate kinase isoform M2 to suppress the Warburg effect and tumorigenicity in hepatocellular carcinoma. Oncogene 34:3946–3956

[4] Davis ME, Gack MU (2015) Ubiquitination in the antiviral immune response. Virology 479–480:52–65

[5] Dias A, Bouvier D, Crepin T, McCarthy AA, Hart DJ, Baudin F, Cusack S, Ruigrok RW (2009) The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit. Nature 458:914–918

[6] Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, Coyle AJ, Liao SM, Maniatis T (2003) IKK epsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 4:491–496

[7] Gabriel G, Dauber B, Wolff T, Planz O, Klenk HD, Stech J (2005) The viral polymerase mediates adaptation of an avian influenza virus to a mammalian host. Proc Natl Acad Sci USA 102:18590–18595

[8] Gack MU, Albrecht RA, Urano T, Inn KS, Huang IC, Carnero E, Farzan M, Inoue S, Jung JU, Garcia-Sastre A (2009) Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I. Cell Host Microbe 5:439–449

[9] Graef KM, Vreede FT, Lau YF, McCall AW, Carr SM, Subbarao K, Fodor E (2010) The PB2 subunit of the influenza virus RNA polymerase affects virulence by interacting with the mitochondrial antiviral signaling protein and inhibiting expression of beta interferon. J Virol 84:8433–8445

[10] Hacker H, Tseng PH, Karin M (2011) Expanding TRAF function: TRAF3 as a tri-faced immune regulator. Nat Rev Immunol 11:457–468

[11] Hatakeyama S (2017) TRIM family proteins: roles in autophagy, immunity, and carcinogenesis. Trends Biochem Sci 42:297–311

[12] Hatta M, Gao P, Halfmann P, Kawaoka Y (2001) Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. Science 293:1840–1842

[13] Iwai A, Shiozaki T, Kawai T, Akira S, Kawaoka Y, Takada A, Kida H, Miyazaki T (2010) Influenza A virus polymerase inhibits type I interferon induction by binding to interferon beta promoter stimulator 1. J Biol Chem 285:32064–32074

[14] Jiao P, Tian G, Li Y, Deng G, Jiang Y, Liu C, Liu W, Bu Z, Kawaoka Y, Chen H (2008) A single-amino-acid substitution in the NS1 protein changes the pathogenicity of H5N1 avian influenza viruses in mice. J Virol 82:1146–1154

[15] Joazeiro CAP, Weissman AM (2000) RING finger proteins: mediators of ubiquitin ligase activity. Cell 102:549–552

[16] Kawai T, Akira S (2006) Innate immune recognition of viral infection. Nat Immunol 7:131–137

[17] Kawai T, Takahashi K, Sato S, Coban C, Kumar H, Kato H, Ishii KJ, Takeuchi O, Akira S (2005) IPS-1, an adaptor triggering RIG-Iand Mda5-mediated type I interferon induction. Nat Immunol 6:981–988

[18] Kimura F, Suzu S, Nakamura Y, Nakata Y, Yamada M, Kuwada N, Matsumura T, Yamashita T, Ikeda T, Sato K (2003) Cloning and characterization of a novel RING-B-box-coiled-coil protein with apoptotic function. J Biol Chem 278:25046–25054

[19] Kowalinski E, Lunardi T, McCarthy AA, Louber J, Brunel J, Grigorov B, Gerlier D, Cusack S (2011) Structural basis for the activation of innate immune pattern-recognition receptor RIG-I by viral RNA. Cell 147:423–435

[20] Li Z, Chen H, Jiao P, Deng G, Tian G, Li Y, Hoffmann E, Webster RG, Matsuoka Y, Yu K (2005) Molecular basis of replication of duck H5N1 influenza viruses in a mammalian mouse model. J Virol 79:12058–12064

[21] Li Z, Jiang Y, Jiao P, Wang A, Zhao F, Tian G, Wang X, Yu K, Bu Z, Chen H (2006) The NS1 gene contributes to the virulence of H5N1 avian influenza viruses. J Virol 80:11115–11123

[22] Li Y, Wu H, Wu W, Zhuo W, Liu WX, Zhang YX, Cheng MZ, Chen YG, Gao N, Yu HT (2014) Structural insights into the TRIM family of ubiquitin E3 ligases. Cell Res 24:762–765

[23] Liang LB, Jiang L, Li JP, Zhao QQ, Wang JG, He XJ, Huang SY, Wang Q, Zhao YH, Wang GW (2019) Low polymerase activity attributed to PA drives the acquisition of the PB2 E627K mutation of H7N9 avian influenza virus in mammals. mBio 10: e01162–19

[24] Liedmann S, Hrincius ER, Guy C, Anhlan D, Dierkes R, Carter R, Wu G, Staeheli P, Green DR, Wolff T (2014) Viral suppressors of the RIG-I-mediated interferon response are prepackaged in influenza virions. Nat Commun 5:5645

[25] Loo YM, Gale M (2011) Immune signaling by RIG-I-like receptors. Immunity 34:680–692

[26] Luo WY, Zhang J, Liang LB, Wang GW, Li QB, Zhu PY, Zhou Y, Li JP, Zhao YH, Sun N (2018) Phospholipid scramblase 1 interacts with influenza A virus NP, impairing its nuclear import and thereby suppressing virus replication. PLoS Pathog 14:e1006851

[27] Mao AP, Li S, Zhong B, Li Y, Yan J, Li Q, Teng C, Shu HB (2010) Virus-triggered ubiquitination of TRAF3/6 by cIAP1/2 is essential for induction of interferon-beta (IFN-beta) and cellular antiviral response. J Biol Chem 285:9470–9476

[28] Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, Bartenschlager R, Tschopp R (2005) Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437:1167–1172

[29] Mibayashi M, Martinez-Sobrido L, Loo YM, Cardenas WB, Gale M Jr, Garcia-Sastre A (2007) Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus. J Virol 81:514–524

[30] Min JY, Santos C, Fitch A, Twaddle A, Toyoda Y, DePasse JV, Ghedin E, Subbarao K (2013) Mammalian adaptation in the PB2 gene of Avian H5N1 influenza virus. J Virol 87:10884–10888

[31] Moeller A, Kirchdoerfer RN, Potter CS, Carragher B, Wilson IA (2012) Organization of the influenza virus replication machinery. Science 338:1631–1634

[32] Mukaigawa J, Nayak DP (1991) Two signals mediate nuclear localization of influenza virus (A/WSN/33) polymerase basic protein 2. J Virol 65:245–253

[33] Ozato K, Shin DM, Chang TH, Morse HC (2008) TRIM family proteins and their emerging roles in innate immunity. Nat Rev Immunol 8:849–860

[34] Pickart CM, Fushman D (2004) Polyubiquitin chains: polymeric protein signals. Curr Opin Chem Biol 8:610–616

[35] Plotch SJ, Bouloy M, Ulmanen I, Krug RM (1981) A unique cap(m7G pppXm)-dependent influenza virion endonuclease cleaves capped RNAs to generate the primers that initiate viral RNA transcription. Cell 23:847–858

[36] Qian W, Wei X, Guo K, Li Y, Lin X, Zou Z, Zhou H, Jin M (2017) The C-terminal effector domain of non-structural protein 1 of influenza A virus blocks IFN-β production by targeting TNF receptorassociated factor 3. Front Immunol 8:779

[37] Rajsbaum R, Garcia-Sastre A, Versteeg GA (2014) TRIMmunity: the roles of the TRIM E3-ubiquitin ligase family in innate antiviral immunity. J Mol Biol 426:1265–1284

[38] Rieser E, Cordier SM, Walczak H (2013) Linear ubiquitination: a newly discovered regulator of cell signalling. Trends Biochem Sci 38:94–102

[39] Sadowski M, Sarcevic B (2010) Mechanisms of mono- and polyubiquitination: Ubiquitination specificity depends on compatibility between the E2 catalytic core and amino acid residues proximal to the lysine. Cell Div 5:19

[40] Saha SK, Pietras EM, He JQ, Kang JR, Liu SY, Oganesyan G, Shahangian A, Zarnegar B, Shiba TL, Wang Y (2006) Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif. EMBO J 25:3257–3263

[41] Seth RB, Sun LJ, Ea CK, Chen ZJ (2005) Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappa B and IRF3. Cell 122:669–682

[42] Subbarao EK, London W, Murphy BR (1993) A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. J Virol 67:1761–1764

[43] Thompson MR, Kaminski JJ, Kurt-Jones EA, Fitzgerald KA (2011) Pattern recognition receptors and the innate immune response to viral infection. Viruses 3:920–940

[44] Tseng PH, Matsuzawa A, Zhang W, Mino T, Vignali DA, Karin M (2010) Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines. Nat Immunol 11:70–75

[45] van Gent M, Sparrer KMJ, Gack MU (2018) TRIM proteins and their roles in antiviral host defenses. Annu Rev Virol 5:385–405

[46] Varga ZT, Ramos I, Hai R, Schmolke M, Garcia-Sastre A, Fernandez-Sesma A, Palese P (2011) The influenza virus protein PB1-F2 inhibits the induction of type I interferon at the level of the MAVS adaptor protein. PLoS Pathog 7:e1002067

[47] Wang Y, Shaked I, Stanford SM, Zhou W, Curtsinger JM, Mikulski Z, Shaheen ZR, Cheng G, Sawatzke K, Campbell AM (2013) The autoimmunity-associated gene PTPN22 potentiates toll-like receptor-driven, type 1 interferon-dependent immunity. Immunity 39:111–122

[48] Wang Y, Yan S, Yang B, Wang Y, Zhou H, Lian Q, Sun B (2015) TRIM35 negatively regulates TLR7- and TLR9-mediated type I interferon production by targeting IRF7. FEBS Lett 589:1322–1330

[49] Weber M, Gawanbacht A, Habjan M, Rang A, Bomer C, Schmidt AM, Veitinger S, Jacob R, Devignot S, Kochs G (2013) Incoming RNA virus nucleocapsids containing a 5′-triphosphorylated genome activate RIG-I and antiviral signaling. Cell Host Microbe 13:336–346

[50] Xu LG, Wang YY, Han KJ, Li LY, Zhai ZH, Shu HB (2005) VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell 19:727–740

[51] Yamayoshi S, Watanabe M, Goto H, Kawaoka Y (2016) Identification of a novel viral protein expressed from the PB2 segment of influenza A virus. J Virol 90:444–456

[52] Yi C, Zhao Z, Wang S, Sun X, Zhang D, Sun X, Zhang A, Jin M (2017) Influenza A virus PA antagonizes interferon-beta by interacting with interferon regulatory factor 3. Front Immunol 8:1051

[53] Yoneyama M, Onomoto K, Jogi M, Akaboshi T, Fujita T (2015) Viral RNA detection by RIG-I-like receptors. Curr Opin Immunol 32:48–53

[54] Yuan P, Bartlam M, Lou Z, Chen S, Zhou J, He X, Lv Z, Ge R, Li X, Deng T (2009) Crystal structure of an avian influenza polymerase PA(N) reveals an endonuclease active site. Nature 458:909–913

[55] Zhang T, Ye Z, Yang X, Qin Y, Hu Y, Tong X, Lai W, Ye X (2017) NEDDylation of PB2 reduces its stability and blocks the replication of influenza A virus. Sci Rep 7:43691

[56] Zhu Q, Yang H, Chen W, Cao W, Zhong G, Jiao P, Deng G, Yu K, Yang C (2008) A naturally occurring deletion in its NS gene contributes to the attenuation of an H5N1 swine influenza virus in chickens. J Virol 82:220–228

[57] Zhu K, Wang X, Ju LG, Zhu Y, Yao J, Wang Y, Wu M, Li LY (2015) WDR82 negatively regulates cellular antiviral response by mediating TRAF3 polyubiquitination in multiple cell lines. J Immunol 195:5358–5366

[58] Zhu PY, Liang LB, Shao XY, Luo WY, Jiang ST, Zhao QQ, Sun N, Zhao YH, Li JP, Wang JG (2017) Host cellular protein TRAPPC6A delta interacts with influenza A virus M2 protein and regulates viral propagation by modulating M2 trafficking. J Virol 91:e01757-16

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