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Volume 96, Issue 11

Suppression of type I and type III IFN signalling by NSs protein of severe fever with thrombocytopenia syndrome virus through inhibition of STAT1 phosphorylation and activation Free

Abstract

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne pathogen causing significant morbidity and mortality in Asia. NSs protein of SFTSV is known to perturb type I IFN induction and signalling, but the mechanism remains to be fully understood. Here, we showed the suppression of both type I and type III IFN signalling by SFTSV NSs protein is mediated through inhibition of STAT1 phosphorylation and activation. Infection with live SFTSV or expression of NSs potently suppressed IFN-stimulated genes but not NFκB activation. NSs was capable of counteracting the activity of IFN-α1, IFN-β, IFN-λ1 and IFN-λ2. Mechanistically, NSs associated with STAT1 and STAT2, mitigated IFN-β-induced phosphorylation of STAT1 at S727, and reduced the expression and activity of STAT1 protein in IFN-β-treated cells, resulting in the inhibition of STAT1 and STAT2 recruitment to IFN-stimulated promoters. Taken together, SFTSV NSs protein is an IFN antagonist that suppresses phosphorylation and activation of STAT1.

  • Received:
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© 2015 The Authors
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2015-11-01
2024-04-27
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References

  1. Bao C.J., Guo X.L., Qi X., Hu J.L., Zhou M.H., Varma J.K., Cui L.B., Yang H.T., Jiao Y.J., other authors. 2011; A family cluster of infections by a newly recognized bunyavirus in eastern China, 2007: further evidence of person-to-person transmission. Clin Infect Dis 53:1208–1214 [View Article][PubMed]
     [Google Scholar]
  2. Billecocq A., Spiegel M., Vialat P., Kohl A., Weber F., Bouloy M., Haller O. 2004; NSs protein of Rift Valley fever virus blocks interferon production by inhibiting host gene transcription. J Virol 78:9798–9806 [View Article][PubMed]
     [Google Scholar]
  3. Cárdenas W.B., Loo Y.M., Gale M. Jr, Hartman A.L., Kimberlin C.R., Martínez-Sobrido L., Saphire E.O., Basler C.F. 2006; Ebola virus VP35 protein binds double-stranded RNA and inhibits α/β interferon production induced by RIG-I signaling. J Virol 80:5168–5178 [View Article][PubMed]
     [Google Scholar]
  4. Chan C.P., Mak T.Y., Chin K.T., Ng I.O.L., Jin D.Y. 2010; N-linked glycosylation is required for optimal proteolytic activation of membrane-bound transcription factor CREB-H. J Cell Sci 123:1438–1448 [View Article][PubMed]
     [Google Scholar]
  5. Chin K.T., Zhou H.J., Wong C.M., Lee J.M., Chan C.P., Qiang B.Q., Yuan J.G., Ng I.O.L., Jin D.Y. 2005; The liver-enriched transcription factor CREB-H is a growth suppressor protein underexpressed in hepatocellular carcinoma. Nucleic Acids Res 33:1859–1873 [View Article][PubMed]
     [Google Scholar]
  6. Chun A.C.S., Kok K.H., Jin D.Y. 2013; REV7 is required for anaphase-promoting complex-dependent ubiquitination and degradation of translesion DNA polymerase REV1. Cell Cycle 12:365–378 [View Article][PubMed]
     [Google Scholar]
  7. Deng B., Zhang S., Geng Y., Zhang Y., Wang Y., Yao W., Wen Y., Cui W., Zhou Y., other authors. 2012; Cytokine and chemokine levels in patients with severe fever with thrombocytopenia syndrome virus. PLoS One 7:e41365 [View Article][PubMed]
     [Google Scholar]
  8. Gai Z.T., Zhang Y., Liang M.F., Jin C., Zhang S., Zhu C.B., Li C., Li X.Y., Zhang Q.F., other authors. 2012; Clinical progress and risk factors for death in severe fever with thrombocytopenia syndrome patients. J Infect Dis 206:1095–1102 [View Article][PubMed]
     [Google Scholar]
  9. Habjan M., Pichlmair A. 2015; Cytoplasmic sensing of viral nucleic acids. Curr Opin Virol 11:31–37 [View Article][PubMed]
     [Google Scholar]
  10. Hoffmann H.H., Schneider W.M., Rice C.M. 2015; Interferons and viruses: an evolutionary arms race of molecular interactions. Trends Immunol 36:124–138 [View Article][PubMed]
     [Google Scholar]
  11. Ikegami T., Makino S. 2011; The pathogenesis of Rift Valley fever. Viruses 3:493–519 [View Article][PubMed]
     [Google Scholar]
  12. Ikegami T., Narayanan K., Won S., Kamitani W., Peters C.J., Makino S. 2009; Rift Valley fever virus NSs protein promotes post-transcriptional downregulation of protein kinase PKR and inhibits eIF2α phosphorylation. PLoS Pathog 5:e1000287 [View Article][PubMed]
     [Google Scholar]
  13. Jin C., Liang M., Ning J., Gu W., Jiang H., Wu W., Zhang F., Li C., Zhang Q., other authors. 2012; Pathogenesis of emerging severe fever with thrombocytopenia syndrome virus in C57/BL6 mouse model. Proc Natl Acad Sci U S A 109:10053–10058 [View Article][PubMed]
     [Google Scholar]
  14. Jin C., Jiang H., Liang M., Han Y., Gu W., Zhang F., Zhu H., Wu W., Chen T., other authors. 2015; SFTS virus infection in nonhuman primates. J Infect Dis 211:915–925 [View Article][PubMed]
     [Google Scholar]
  15. Kalveram B., Lihoradova O., Indran S.V., Lokugamage N., Head J.A., Ikegami T. 2013; Rift Valley fever virus NSs inhibits host transcription independently of the degradation of dsRNA-dependent protein kinase PKR. Virology 435:415–424 [View Article][PubMed]
     [Google Scholar]
  16. Kim K.H., Yi J., Kim G., Choi S.J., Jun K.I., Kim N.H., Choe P.G., Kim N.J., Lee J.K., Oh M.D. 2013; Severe fever with thrombocytopenia syndrome, South Korea, 2012. Emerg Infect Dis 19:1892–1894 [View Article][PubMed]
     [Google Scholar]
  17. Kok K.H., Lui P.Y., Ng M.H.J., Siu K.L., Au S.W.N., Jin D.Y. 2011; The double-stranded RNA-binding protein PACT functions as a cellular activator of RIG-I to facilitate innate antiviral response. Cell Host Microbe 9:299–309 [View Article][PubMed]
     [Google Scholar]
  18. Kunsch C., Rosen C.A. 1993; NF-κ B subunit-specific regulation of the interleukin-8 promoter. Mol Cell Biol 13:6137–6146[PubMed] [CrossRef]
     [Google Scholar]
  19. Li D.X. 2015; Severe fever with thrombocytopenia syndrome: a newly discovered emerging infectious disease. Clin Microbiol Infect 21:614–620 [View Article][PubMed]
     [Google Scholar]
  20. Lin R., Heylbroeck C., Pitha P.M., Hiscott J. 1998; Virus-dependent phosphorylation of the IRF-3 transcription factor regulates nuclear translocation, transactivation potential, and proteasome-mediated degradation. Mol Cell Biol 18:2986–2996[PubMed] [CrossRef]
     [Google Scholar]
  21. Liu Q., He B., Huang S.Y., Wei F., Zhu X.Q. 2014; Severe fever with thrombocytopenia syndrome, an emerging tick-borne zoonosis. Lancet Infect Dis 14:763–772 [View Article][PubMed]
     [Google Scholar]
  22. McMullan L.K., Folk S.M., Kelly A.J., MacNeil A., Goldsmith C.S., Metcalfe M.G., Batten B.C., Albariño C.G., Zaki S.R., other authors. 2012; A new phlebovirus associated with severe febrile illness in Missouri. N Engl J Med 367:834–841 [View Article][PubMed]
     [Google Scholar]
  23. Muehlenbachs A., Fata C.R., Lambert A.J., Paddock C.D., Velez J.O., Blau D.M., Staples J.E., Karlekar M.B., Bhatnagar J., other authors. 2014; Heartland virus-associated death in Tennessee. Clin Infect Dis 59:845–850 [View Article][PubMed]
     [Google Scholar]
  24. Ng M.H.J., Ho T.H., Kok K.H., Siu K.L., Li J., Jin D.Y. 2011; MIP-T3 is a negative regulator of innate type I IFN response. J Immunol 187:6473–6482 [View Article][PubMed]
     [Google Scholar]
  25. Ning Y.J., Wang M., Deng M., Shen S., Liu W., Cao W.C., Deng F., Wang Y.Y., Hu Z., Wang H. 2014; Viral suppression of innate immunity via spatial isolation of TBK1/IKKϵ from mitochondrial antiviral platform. J Mol Cell Biol 6:324–337 [View Article][PubMed]
     [Google Scholar]
  26. Ning Y.J., Feng K., Min Y.Q., Cao W.C., Wang M., Deng F., Hu Z., Wang H. 2015; Disruption of type I interferon signaling by the nonstructural protein of severe fever with thrombocytopenia syndrome virus via the hijacking of STAT2 and STAT1 into inclusion bodies. J Virol 89:4227–4236 [View Article][PubMed]
     [Google Scholar]
  27. Niu G., Li J., Liang M., Jiang X., Jiang M., Yin H., Wang Z., Li C., Zhang Q., other authors. 2013; Severe fever with thrombocytopenia syndrome virus among domesticated animals, China. Emerg Infect Dis 19:756–763[PubMed]
     [Google Scholar]
  28. Precious B., Childs K., Fitzpatrick-Swallow V., Goodbourn S., Randall R.E. 2005; Simian virus 5 V protein acts as an adaptor, linking DDB1 to STAT2, to facilitate the ubiquitination of STAT1. J Virol 79:13434–13441 [View Article][PubMed]
     [Google Scholar]
  29. Qu B., Qi X., Wu X., Liang M., Li C., Cardona C.J., Xu W., Tang F., Li Z., other authors. 2012; Suppression of the interferon and NF-κB responses by severe fever with thrombocytopenia syndrome virus. J Virol 86:8388–8401 [View Article][PubMed]
     [Google Scholar]
  30. Randall R.E., Goodbourn S. 2008; Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol 89:1–47 [View Article][PubMed]
     [Google Scholar]
  31. Samuel C.E. 2011; Adenosine deaminases acting on RNA (ADARs) are both antiviral and proviral. Virology 411:180–193 [View Article][PubMed]
     [Google Scholar]
  32. Santiago F.W., Covaleda L.M., Sanchez-Aparicio M.T., Silvas J.A., Diaz-Vizarreta A.C., Patel J.R., Popov V., Yu X.J., García-Sastre A., Aguilar P.V. 2014; Hijacking of RIG-I signaling proteins into virus-induced cytoplasmic structures correlates with the inhibition of type I interferon responses. J Virol 88:4572–4585 [View Article][PubMed]
     [Google Scholar]
  33. Schneider W.M., Chevillotte M.D., Rice C.M. 2014; Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol 32:513–545 [View Article][PubMed]
     [Google Scholar]
  34. Schreiber E., Matthias P., Müller M.M., Schaffner W. 1989; Rapid detection of octamer binding proteins with ‘mini-extracts’, prepared from a small number of cells. Nucleic Acids Res 17:6419 [View Article][PubMed]
     [Google Scholar]
  35. Sun Y., Jin C., Zhan F., Wang X., Liang M., Zhang Q., Ding S., Guan X., Huo X., other authors. 2012; Host cytokine storm is associated with disease severity of severe fever with thrombocytopenia syndrome. J Infect Dis 206:1085–1094 [View Article][PubMed]
     [Google Scholar]
  36. Takahashi T., Maeda K., Suzuki T., Ishido A., Shigeoka T., Tominaga T., Kamei T., Honda M., Ninomiya D., other authors. 2014; The first identification and retrospective study of Severe Fever with Thrombocytopenia Syndrome in Japan. J Infect Dis 209:816–827 [View Article][PubMed]
     [Google Scholar]
  37. Takaoka A., Tanaka N., Mitani Y., Miyazaki T., Fujii H., Sato M., Kovarik P., Decker T., Schlessinger J., Taniguchi T. 1999; Protein tyrosine kinase Pyk2 mediates the Jak-dependent activation of MAPK and Stat1 in IFN-γ, but not IFN-α, signaling. EMBO J 18:2480–2488 [View Article][PubMed]
     [Google Scholar]
  38. Tang H.M.V., Gao W.W., Chan C.P., Siu Y.T., Wong C.M., Kok K.H., Ching Y.P., Takemori H., Jin D.Y. 2013; LKB1 tumor suppressor and salt-inducible kinases negatively regulate human T-cell leukemia virus type 1 transcription. Retrovirology 10:40 [View Article][PubMed]
     [Google Scholar]
  39. Tang H.M.V., Gao W.W., Chan C.P., Cheng Y., Chaudhary V., Deng J.J., Yuen K.S., Wong C.M., Ng I.O.L., other authors. 2014; Requirement of CRTC1 coactivator for hepatitis B virus transcription. Nucleic Acids Res 42:12455–12468 [View Article][PubMed]
     [Google Scholar]
  40. Walter C.T., Barr J.N. 2011; Recent advances in the molecular and cellular biology of bunyaviruses. J Gen Virol 92:2467–2484 [View Article][PubMed]
     [Google Scholar]
  41. Wang J., Selleck P., Yu M., Ha W., Rootes C., Gales R., Wise T., Crameri S., Chen H., other authors. 2014; Novel phlebovirus with zoonotic potential isolated from ticks. Emerg Infect Dis 20:1040–1043[PubMed] [CrossRef]
     [Google Scholar]
  42. Wen Z., Zhong Z., Darnell J.E., Jr. 1995; Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82:241–250 [View Article][PubMed]
     [Google Scholar]
  43. Wickremasinghe M.I., Thomas L.H., O'Kane C.M., Uddin J., Friedland J.S. 2004; Transcriptional mechanisms regulating alveolar epithelial cell-specific CCL5 secretion in pulmonary tuberculosis. J Biol Chem 279:27199–27210 [View Article][PubMed]
     [Google Scholar]
  44. Wong L.H., Sim H., Chatterjee-Kishore M., Hatzinisiriou I., Devenish R.J., Stark G., Ralph S.J. 2002; Isolation and characterization of a human STAT1 gene regulatory element. Inducibility by interferon (IFN) types I and II and role of IFN regulatory factor-1. J Biol Chem 277:19408–19417 [View Article][PubMed]
     [Google Scholar]
  45. Wu X., Qi X., Qu B., Zhang Z., Liang M., Li C., Cardona C.J., Li D., Xing Z. 2014; Evasion of antiviral immunity through sequestering of TBK1/IKKϵ/IRF3 into viral inclusion bodies. J Virol 88:3067–3076 [View Article][PubMed]
     [Google Scholar]
  46. Yu X.J., Liang M.F., Zhang S.Y., Liu Y., Li J.D., Sun Y.L., Zhang L., Zhang Q.F., Popov V.L., other authors. 2011; Fever with thrombocytopenia associated with a novel bunyavirus in China. N Engl J Med 364:1523–1532 [View Article][PubMed]
     [Google Scholar]
  47. Yuen K.S., Chan C.P., Wong N.H., Ho C.H., Ho T.H., Lei T., Deng W., Tsao S.W., Chen H., other authors. 2015; CRISPR/Cas9-mediated genome editing of Epstein-Barr virus in human cells. J Gen Virol 96:626–636 [View Article][PubMed]
     [Google Scholar]
  48. Yun S.M., Lee W.G., Ryou J., Yang S.C., Park S.W., Roh J.Y., Lee Y.J., Park C., Han M.G. 2014; Severe fever with thrombocytopenia syndrome virus in ticks collected from humans, South Korea, 2013. Emerg Infect Dis 20:1358–1361 [View Article][PubMed]
     [Google Scholar]
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Suppression of type I and type III IFN signalling by NSs protein of severe fever with thrombocytopenia syndrome virus through inhibition of STAT1 phosphorylation and activation
J. Gen. Virol. 96, 3204 (2015); https://doi.org/10.1099/jgv.0.000280
/content/journal/jgv/10.1099/jgv.0.000280
/content/journal/jgv/10.1099/jgv.0.000280
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