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Volume 96, Issue 10

Porcine reproductive and respiratory syndrome virus 3C protease cleaves the mitochondrial antiviral signalling complex to antagonize IFN-β expression Open Access

Abstract

Porcine reproductive and respiratory syndrome, a highly infectious disease caused by porcine reproductive and respiratory syndrome virus (PRRSV), has developed various strategies to evade the host innate immune response, including the suppression of type I IFN activation. The mitochondrial antiviral signalling protein (MAVS) is an important bridging adaptor of retinoic acid-inducible gene I/melanoma differentiation-associated protein 5 signalling pathways. Here, we demonstrated that the 3C-like protease (3CLSP) of PRRSV prevented the induction of IFN-β by cleaving MAVS in a proteasome- and caspase-independent manner. Moreover, this cleavage ability was dependent on the protease activity of 3CLSP. Mutations specifically disrupting the cysteine protease activity of 3CLSP eliminated MAVS cleavage and the inhibition of IFN induction. Subsequently, we determined that 3CLSP cleaved MAVS at Glu268. Remarkably, a MAVS point mutation at Glu268 rendered MAVS resistant to 3CLSP cleavage. These results reveal a novel PRRSV mechanism to escape host immunity by directly cleaving MAVS.

  • Received:
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© 2015 The Authors
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2015-10-01
2024-04-25
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References

  1. Albina E. 1997; Epidemiology of porcine reproductive and respiratory syndrome (PRRS): an overview. Vet Microbiol 55:309–316 [View Article][PubMed]
     [Google Scholar]
  2. Albina E., Piriou L., Hutet E., Cariolet R., L'Hospitalier R. 1998; Immune responses in pigs infected with porcine reproductive and respiratory syndrome virus (PRRSV). Vet Immunol Immunopathol 61:49–66 [View Article][PubMed]
     [Google Scholar]
  3. Beura L.K., Sarkar S.N., Kwon B., Subramaniam S., Jones C., Pattnaik A.K., Osorio F.A. 2010; Porcine reproductive and respiratory syndrome virus nonstructural protein 1β modulates host innate immune response by antagonizing IRF3 activation. J Virol 84:1574–1584 [View Article][PubMed]
     [Google Scholar]
  4. Bowie A.G., Unterholzner L. 2008; Viral evasion and subversion of pattern-recognition receptor signalling. Nat Rev Immunol 8:911–922 [View Article][PubMed]
     [Google Scholar]
  5. Buddaert W., Van Reeth K., Pensaert M. 1998; In vivo and in vitro interferon (IFN) studies with the porcine reproductive and respiratory syndrome virus (PRRSV). Adv Exp Med Biol 440:461–467 [View Article][PubMed]
     [Google Scholar]
  6. Chen Z., Rijnbrand R., Jangra R.K., Devaraj S.G., Qu L., Ma Y., Lemon S.M., Li K. 2007; Ubiquitination and proteasomal degradation of interferon regulatory factor-3 induced by Npro from a cytopathic bovine viral diarrhea virus. Virology 366:277–292 [View Article][PubMed]
     [Google Scholar]
  7. Clementz M.A., Chen Z., Banach B.S., Wang Y., Sun L., Ratia K., Baez-Santos Y.M., Wang J., Takayama J., other authors. 2010; Deubiquitinating and interferon antagonism activities of coronavirus papain-like proteases. J Virol 84:4619–4629 [View Article][PubMed]
     [Google Scholar]
  8. Drahos J., Racaniello V.R. 2009; Cleavage of IPS-1 in cells infected with human rhinovirus. J Virol 83:11581–11587 [View Article][PubMed]
     [Google Scholar]
  9. Fang Y., Snijder E.J. 2010; The PRRSV replicase: exploring the multifunctionality of an intriguing set of nonstructural proteins. Virus Res 154:61–76 [View Article][PubMed]
     [Google Scholar]
  10. Goodbourn S., Didcock L., Randall R.E. 2000; Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures. J Gen Virol 81:2341–2364[PubMed] [CrossRef]
     [Google Scholar]
  11. Halbur P.G., Paul P.S., Meng X.J., Lum M.A., Andrews J.J., Rathje J.A. 1996; Comparative pathogenicity of nine US porcine reproductive and respiratory syndrome virus (PRRSV) isolates in a five-week-old cesarean-derived, colostrum-deprived pig model. J Vet Diagn Invest 8:11–20 [View Article][PubMed]
     [Google Scholar]
  12. Hou F., Sun L., Zheng H., Skaug B., Jiang Q.X., Chen Z.J. 2011; MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell 146:448–461 [View Article][PubMed]
     [Google Scholar]
  13. Huang C., Zhang Q., Guo X.K., Yu Z.B., Xu A.T., Tang J., Feng W.H. 2014; Porcine reproductive and respiratory syndrome virus nonstructural protein 4 antagonizes beta interferon expression by targeting the NF-κB essential modulator. J Virol 88:10934–10945 [View Article][PubMed]
     [Google Scholar]
  14. Kawai T., Akira S. 2006; Innate immune recognition of viral infection. Nat Immunol 7:131–137 [View Article][PubMed]
     [Google Scholar]
  15. Kim O., Sun Y., Lai F.W., Song C., Yoo D. 2010; Modulation of type I interferon induction by porcine reproductive and respiratory syndrome virus and degradation of CREB-binding protein by non-structural protein 1 in MARC-145 and HeLa cells. Virology 402:315–326 [View Article][PubMed]
     [Google Scholar]
  16. Krebs D.L., Hilton D.J. 2001; SOCS proteins: negative regulators of cytokine signaling. Stem Cells 19:378–387 [View Article][PubMed]
     [Google Scholar]
  17. Lei X., Sun Z., Liu X., Jin Q., He B., Wang J. 2011; Cleavage of the adaptor protein TRIF by enterovirus 71 3C inhibits antiviral responses mediated by Toll-like receptor 3. J Virol 85:8811–8818 [View Article][PubMed]
     [Google Scholar]
  18. Li X.D., Sun L., Seth R.B., Pineda G., Chen Z.J. 2005; Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc Natl Acad Sci U S A 102:17717–17722 [View Article][PubMed]
     [Google Scholar]
  19. Luo R., Xiao S., Jiang Y., Jin H., Wang D., Liu M., Chen H., Fang L. 2008; Porcine reproductive and respiratory syndrome virus (PRRSV) suppresses interferon-β-production by interfering with the RIG-I signaling pathway. Mol Immunol 45:2839–2846 [View Article][PubMed]
     [Google Scholar]
  20. Miller L.C., Laegreid W.W., Bono J.L., Chitko-McKown C.G., Fox J.M. 2004; Interferon type I response in porcine reproductive and respiratory syndrome virus-infected MARC-145 cells. Arch Virol 149:2453–2463 [View Article][PubMed]
     [Google Scholar]
  21. Moresco E.M., Vine D.L., Beutler B. 2011; Prion-like behavior of MAVS in RIG-I signaling. Cell Res 21:1643–1645 [View Article][PubMed]
     [Google Scholar]
  22. Mukherjee A., Morosky S.A., Delorme-Axford E., Dybdahl-Sissoko N., Oberste M.S., Wang T., Coyne C.B. 2011; The coxsackievirus B 3C protease cleaves MAVS and TRIF to attenuate host type I interferon and apoptotic signaling. PLoS Pathog 7:e1001311 [View Article][PubMed]
     [Google Scholar]
  23. Murtaugh M.P., Xiao Z., Zuckermann F. 2002; Immunological responses of swine to porcine reproductive and respiratory syndrome virus infection. Viral Immunol 15:533–547 [View Article][PubMed]
     [Google Scholar]
  24. Music N., Gagnon C.A. 2010; The role of porcine reproductive and respiratory syndrome (PRRS) virus structural and non-structural proteins in virus pathogenesis. Anim Health Res Rev 11:135–163 [View Article][PubMed]
     [Google Scholar]
  25. Neumann E.J., Kliebenstein J.B., Johnson C.D., Mabry J.W., Bush E.J., Seitzinger A.H., Green A.L., Zimmerman J.J. 2005; Assessment of the economic impact of porcine reproductive and respiratory syndrome on swine production in the United States. J Am Vet Med Assoc 227:385–392 [View Article][PubMed]
     [Google Scholar]
  26. Parera M., Martrus G., Franco S., Clotet B., Martinez M.A. 2012; Canine hepacivirus NS3 serine protease can cleave the human adaptor proteins MAVS and TRIF. PLoS One 7:e42481 [View Article][PubMed]
     [Google Scholar]
  27. Qu L., Feng Z., Yamane D., Liang Y., Lanford R.E., Li K., Lemon S.M. 2011; Disruption of TLR3 signaling due to cleavage of TRIF by the hepatitis A virus protease-polymerase processing intermediate, 3CD. PLoS Pathog 7:e1002169 [View Article][PubMed]
     [Google Scholar]
  28. Sadler A.J., Williams B.R. 2008; Interferon-inducible antiviral effectors. Nat Rev Immunol 8:559–568 [View Article][PubMed]
     [Google Scholar]
  29. Scott I., Norris K.L. 2008; The mitochondrial antiviral signaling protein, MAVS, is cleaved during apoptosis. Biochem Biophys Res Commun 375:101–106 [View Article][PubMed]
     [Google Scholar]
  30. Seth R.B., Sun L., Ea C.K., Chen Z.J. 2005; Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-κB and IRF3. Cell 122:669–682 [View Article][PubMed]
     [Google Scholar]
  31. Sun Y., Han M., Kim C., Calvert J.G., Yoo D. 2012; Interplay between interferon-mediated innate immunity and porcine reproductive and respiratory syndrome virus. Viruses 4:424–446 [View Article][PubMed]
     [Google Scholar]
  32. Tian X., Lu G., Gao F., Peng H., Feng Y., Ma G., Bartlam M., Tian K., Yan J., other authors. 2009; Structure and cleavage specificity of the chymotrypsin-like serine protease (3CLSP/nsp4) of porcine reproductive and respiratory syndrome virus (PRRSV). J Mol Biol 392:977–993 [View Article][PubMed]
     [Google Scholar]
  33. Van Reeth K., Labarque G., Nauwynck H., Pensaert M. 1999; Differential production of proinflammatory cytokines in the pig lung during different respiratory virus infections: correlations with pathogenicity. Res Vet Sci 67:47–52 [View Article][PubMed]
     [Google Scholar]
  34. Wang D., Fang L., Li P., Sun L., Fan J., Zhang Q., Luo R., Liu X., Li K., other authors. 2011; The leader proteinase of foot-and-mouth disease virus negatively regulates the type I interferon pathway by acting as a viral deubiquitinase. J Virol 85:3758–3766 [View Article][PubMed]
     [Google Scholar]
  35. Wang B., Xi X., Lei X., Zhang X., Cui S., Wang J., Jin Q., Zhao Z. 2013; Enterovirus 71 protease 2Apro targets MAVS to inhibit anti-viral type I interferon responses. PLoS Pathog 9:e1003231 [View Article][PubMed]
     [Google Scholar]
  36. Yang Y., Liang Y., Qu L., Chen Z., Yi M., Li K., Lemon S.M. 2007; Disruption of innate immunity due to mitochondrial targeting of a picornaviral protease precursor. Proc Natl Acad Sci U S A 104:7253–7258 [View Article][PubMed]
     [Google Scholar]
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Porcine reproductive and respiratory syndrome virus 3C protease cleaves the mitochondrial antiviral signalling complex to antagonize IFN-β expression
J. Gen. Virol. 96, 3049 (2015); https://doi.org/10.1099/jgv.0.000257
/content/journal/jgv/10.1099/jgv.0.000257
/content/journal/jgv/10.1099/jgv.0.000257
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