An Internally Translated MAVS Variant Exposes Its Amino-terminal TRAF-Binding Motifs to Deregulate Interferon Induction

English version České info

Host innate immune signaling plays critical roles in defeating pathogen infection. In response to viral infection, cellular signaling events cumulate in the activation of NF-κB and interferon regulatory factors. How these two signaling ramifications are differentially regulated remains an open question. Here we report an internally translated MAVS variant deregulates IRF activation via exposing N-terminal TRAF-binding motifs. As such, the short form of MAVS efficiently competes for binding to TRAF2 and TRAF6 against full-length MAVS, thereby sequestering key adaptors from the signaling cascades mediated by full-length MAVS. Our study uncovers a delicate regulatory mechanism of truncated proteins bearing key protein-interacting motifs that is enabled by internal translation initiation and potentially other relevant means.

Vyšlo v časopise: An Internally Translated MAVS Variant Exposes Its Amino-terminal TRAF-Binding Motifs to Deregulate Interferon Induction. PLoS Pathog 11(7): e32767. doi:10.1371/journal.ppat.1005060
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1005060

Souhrn

Zdroje

1. Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140 : 805–820. doi: 10.1016/j.cell.2010.01.022 20303872

2. Wu J, Chen ZJ (2014) Innate immune sensing and signaling of cytosolic nucleic acids. Annu Rev Immunol 32 : 461–488. doi: 10.1146/annurev-immunol-032713-120156 24655297

3. Goubau D, Deddouche S, Reis e Sousa C (2013) Cytosolic sensing of viruses. Immunity 38 : 855–869. doi: 10.1016/j.immuni.2013.05.007 23706667

4. Pichlmair A, Schulz O, Tan CP, Naslund TI, Liljestrom P, et al. (2006) RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates. Science 314 : 997–1001. 17038589

5. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, et al. (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441 : 101–105. 16625202

6. Hornung V, Ellegast J, Kim S, Brzozka K, Jung A, et al. (2006) 5'-Triphosphate RNA is the ligand for RIG-I. Science 314 : 994–997. 17038590

7. Xu LG, Wang YY, Han KJ, Li LY, Zhai Z, et al. (2005) VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell 19 : 727–740. 16153868

8. Seth RB, Sun L, Ea CK, Chen ZJ (2005) Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122 : 669–682. 16125763

9. Meylan E, Curran J, Hofmann K, Moradpour D, Binder M, et al. (2005) Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437 : 1167–1172. 16177806

10. Kawai T, Takahashi K, Sato S, Coban C, Kumar H, et al. (2005) IPS-1, an adaptor triggering RIG-I -⁠ and Mda5-mediated type I interferon induction. Nat Immunol 6 : 981–988. 16127453

11. Zandi E, Rothwarf DM, Delhase M, Hayakawa M, Karin M (1997) The IkappaB kinase complex (IKK) contains two kinase subunits, IKKalpha and IKKbeta, necessary for IkappaB phosphorylation and NF-kappaB activation. Cell 91 : 243–252. 9346241

12. Chen ZJ, Parent L, Maniatis T (1996) Site-specific phosphorylation of IkappaBalpha by a novel ubiquitination-dependent protein kinase activity. Cell 84 : 853–862. 8601309

13. Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, et al. (2003) IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 4 : 491–496. 12692549

14. Sharma S, tenOever BR, Grandvaux N, Zhou GP, Lin R, et al. (2003) Triggering the interferon antiviral response through an IKK-related pathway. Science 300 : 1148–1151. 12702806

15. Feng P, Moses A, Fruh K (2013) Evasion of adaptive and innate immune response mechanisms by gamma-herpesviruses. Curr Opin Virol 3 : 285–295. doi: 10.1016/j.coviro.2013.05.011 23735334

16. Johnson CL, Gale M Jr. (2006) CARD games between virus and host get a new player. Trends Immunol 27 : 1–4. 16309964

17. Kell AM, Gale M Jr. (2015) RIG-I in RNA virus recognition. Virology.

18. Li K, Foy E, Ferreon JC, Nakamura M, Ferreon AC, et al. (2005) Immune evasion by hepatitis C virus NS4/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. Proc Natl Acad Sci U S A 102 : 2992–2997. 15710891

19. Li XD, Sun L, Seth RB, Pineda G, Chen ZJ (2005) Hepatitis C virus protease NS4/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc Natl Acad Sci U S A 102 : 17717–17722. 16301520

20. Yang Y, Liang Y, Qu L, Chen Z, Yi M, et al. (2007) Disruption of innate immunity due to mitochondrial targeting of a picornaviral protease precursor. Proc Natl Acad Sci U S A 104 : 7253–7258. 17438296

21. Wang B, Xi X, Lei X, Zhang X, Cui S, et al. (2013) Enterovirus 71 protease 2Apro targets MAVS to inhibit anti-viral type I interferon responses. PLoS Pathog 9: e1003231. doi: 10.1371/journal.ppat.1003231 23555247

22. Dong X, Feng H, Sun Q, Li H, Wu TT, et al. (2010) Murine gamma-herpesvirus 68 hijacks MAVS and IKKbeta to initiate lytic replication. PLoS Pathog 6: e1001001. doi: 10.1371/journal.ppat.1001001 20686657

23. Dong X, Feng P (2011) Murine gamma herpesvirus 68 hijacks MAVS and IKKbeta to abrogate NFkappaB activation and antiviral cytokine production. PLoS Pathog 7: e1002336. doi: 10.1371/journal.ppat.1002336 22110409

24. Dong X, He Z, Durakoglugil D, Arneson L, Shen Y, et al. (2012) Murine gammaherpesvirus 68 evades host cytokine production via replication transactivator-induced RelA degradation. J Virol 86 : 1930–1941. doi: 10.1128/JVI.06127-11 22130545

25. Sun Q, Sun L, Liu HH, Chen X, Seth RB, et al. (2006) The specific and essential role of MAVS in antiviral innate immune responses. Immunity 24 : 633–642. 16713980

26. Chiang JJ, Davis ME, Gack MU (2014) Regulation of RIG-I-like receptor signaling by host and viral proteins. Cytokine Growth Factor Rev 25 : 491–505. doi: 10.1016/j.cytogfr.2014.06.005 25023063

27. He S, Zhao J, Song S, He X, Minassian A, et al. (2015) Viral Pseudo-Enzymes Activate RIG-I via Deamidation to Evade Cytokine Production. Mol Cell.

28. Brubaker SW, Gauthier AE, Mills EW, Ingolia NT, Kagan JC (2014) A bicistronic MAVS transcript highlights a class of truncated variants in antiviral immunity. Cell 156 : 800–811. doi: 10.1016/j.cell.2014.01.021 24529381

29. Zeng W, Sun L, Jiang X, Chen X, Hou F, et al. (2010) Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity. Cell 141 : 315–330. doi: 10.1016/j.cell.2010.03.029 20403326

30. Xu H, He X, Zheng H, Huang LJ, Hou F, et al. (2014) Structural basis for the prion-like MAVS filaments in antiviral innate immunity. Elife 3: e01489. doi: 10.7554/eLife.01489 24569476

31. Hou F, Sun L, Zheng H, Skaug B, Jiang QX, et al. (2011) MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell 146 : 448–461. doi: 10.1016/j.cell.2011.06.041 21782231

32. Ye H, Park YC, Kreishman M, Kieff E, Wu H (1999) The structural basis for the recognition of diverse receptor sequences by TRAF2. Mol Cell 4 : 321–330. 10518213

33. Ye H, Arron JR, Lamothe B, Cirilli M, Kobayashi T, et al. (2002) Distinct molecular mechanism for initiating TRAF6 signalling. Nature 418 : 443–447. 12140561

34. Belgnaoui SM, Paz S, Samuel S, Goulet ML, Sun Q, et al. (2012) Linear ubiquitination of NEMO negatively regulates the interferon antiviral response through disruption of the MAVS-TRAF3 complex. Cell Host Microbe 12 : 211–222. doi: 10.1016/j.chom.2012.06.009 22901541

35. Cho JA, Lee AH, Platzer B, Cross BC, Gardner BM, et al. (2013) The unfolded protein response element IRE1alpha senses bacterial proteins invading the ER to activate RIG-I and innate immune signaling. Cell Host Microbe 13 : 558–569. doi: 10.1016/j.chom.2013.03.011 23684307

36. Hiscott J, Nguyen TL, Arguello M, Nakhaei P, Paz S (2006) Manipulation of the nuclear factor-kappaB pathway and the innate immune response by viruses. Oncogene 25 : 6844–6867. 17072332

37. Liu S, Cai X, Wu J, Cong Q, Chen X, et al. (2015) Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science 347.

38. Liu S, Chen J, Cai X, Wu J, Chen X, et al. (2013) MAVS recruits multiple ubiquitin E3 ligases to activate antiviral signaling cascades. Elife 2: e00785. doi: 10.7554/eLife.00785 23951545

39. Park YC, Burkitt V, Villa AR, Tong L, Wu H (1999) Structural basis for self-association and receptor recognition of human TRAF2. Nature 398 : 533–538. 10206649

40. Gack MU, Kirchhofer A, Shin YC, Inn KS, Liang C, et al. (2008) Roles of RIG-I N-terminal tandem CARD and splice variant in TRIM25-mediated antiviral signal transduction. Proc Natl Acad Sci U S A 105 : 16743–16748. doi: 10.1073/pnas.0804947105 18948594

41. Han KJ, Yang Y, Xu LG, Shu HB (2010) Analysis of a TIR-less splice variant of TRIF reveals an unexpected mechanism of TLR3-mediated signaling. J Biol Chem 285 : 12543–12550. doi: 10.1074/jbc.M109.072231 20200155

42. Saito T, Hirai R, Loo YM, Owen D, Johnson CL, et al. (2007) Regulation of innate antiviral defenses through a shared repressor domain in RIG-I and LGP2. Proc Natl Acad Sci U S A 104 : 582–587. 17190814

43. Vitour D, Meurs EF (2007) Regulation of interferon production by RIG-I and LGP2: a lesson in self-control. Sci STKE 2007: pe20. 17473309

44. Ryabova LA, Pooggin MM, Hohn T (2002) Viral strategies of translation initiation: ribosomal shunt and reinitiation. Prog Nucleic Acid Res Mol Biol 72 : 1–39. 12206450

45. Ryabova LA, Pooggin MM, Hohn T (2006) Translation reinitiation and leaky scanning in plant viruses. Virus Res 119 : 52–62. 16325949

46. Hellen CU, Sarnow P (2001) Internal ribosome entry sites in eukaryotic mRNA molecules. Genes Dev 15 : 1593–1612. 11445534

47. Pestova TV, Kolupaeva VG, Lomakin IB, Pilipenko EV, Shatsky IN, et al. (2001) Molecular mechanisms of translation initiation in eukaryotes. Proc Natl Acad Sci U S A 98 : 7029–7036. 11416183

48. Feng H, Dong X, Negaard A, Feng P (2008) Kaposi's sarcoma-associated herpesvirus K7 induces viral G protein-coupled receptor degradation and reduces its tumorigenicity. PLoS Pathog 4: e1000157. doi: 10.1371/journal.ppat.1000157 18802460

49. Wang Y, Lu X, Zhu L, Shen Y, Chengedza S, et al. (2013) IKK epsilon kinase is crucial for viral G protein-coupled receptor tumorigenesis. Proc Natl Acad Sci U S A 110 : 11139–11144. doi: 10.1073/pnas.1219829110 23771900