1887

Abstract

Human respiratory syncytial virus (RSV), a leading cause of respiratory tract infections in infants, inhibits type I interferon (IFN)-dependent signalling, as well as IFN synthesis. RSV non-structural protein NS1 plays a significant role in this inhibition; however, the mechanism(s) responsible is not fully known. The transcription factor interferon regulatory factor (IRF)-3 is essential for viral-induced IFN-β synthesis. In this study, we found that NS1 protein inhibits IRF-3-dependent gene transcription in constitutively active IRF-3 overexpressing cells, demonstrating that NS1 directly targets IRF-3. Our data also demonstrate that NS1 associates with IRF-3 and its transcriptional coactivator CBP, leading to disrupted association of IRF-3 to CBP and subsequent reduced binding of IRF-3 to the IFN-β promoter without blocking viral-induced IRF-3 phosphorylation, nuclear translocation and dimerization, thereby identifying a novel molecular mechanism by which RSV inhibits IFN-β synthesis.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.032987-0
2011-09-01
2020-07-04
Loading full text...

Full text loading...

/deliver/fulltext/jgv/92/9/2153.html?itemId=/content/journal/jgv/10.1099/vir.0.032987-0&mimeType=html&fmt=ahah

References

  1. Bao X., Kolli D., Liu T., Shan Y., Garofalo R. P., Casola A. 2008a; Human metapneumovirus small hydrophobic protein inhibits NF-κB transcriptional activity. J Virol 82:8224–8229 [CrossRef][PubMed]
    [Google Scholar]
  2. Bao X., Liu T., Shan Y., Li K., Garofalo R. P., Casola A. 2008b ). Human metapneumovirus glycoprotein G inhibits innate immune responses. PLoS Pathog 4:e1000077 [CrossRef][PubMed]
    [Google Scholar]
  3. Barnes B., Lubyova B., Pitha P. M. 2002; On the role of IRF in host defense. J Interferon Cytokine Res 22:59–71 [CrossRef][PubMed]
    [Google Scholar]
  4. Barro M., Patton J. T. 2005; Rotavirus nonstructural protein 1 subverts innate immune response by inducing degradation of IFN regulatory factor 3. Proc Natl Acad Sci U S A 102:4114–4119 [CrossRef][PubMed]
    [Google Scholar]
  5. Casola A., Burger N., Liu T., Jamaluddin M., Brasier A. R., Garofalo R. P. 2001; Oxidant tone regulates RANTES gene expression in airway epithelial cells infected with respiratory syncytial virus. Role in viral-induced interferon regulatory factor activation. J Biol Chem 276:19715–19722 [CrossRef][PubMed]
    [Google Scholar]
  6. Collins P. L., Murphy B. R. 2005; New generation live vaccines against human respiratory syncytial virus designed by reverse genetics. Proc Am Thorac Soc 2:166–173 [CrossRef][PubMed]
    [Google Scholar]
  7. Dragan A. I., Hargreaves V. V., Makeyeva E. N., Privalov P. L. 2007; Mechanisms of activation of interferon regulator factor 3: the role of C-terminal domain phosphorylation in IRF-3 dimerization and DNA binding. Nucleic Acids Res 35:3525–3534 [CrossRef][PubMed]
    [Google Scholar]
  8. Ehrhardt C., Kardinal C., Wurzer W. J., Wolff T., von Eichel-Streiber C., Pleschka S., Planz O., Ludwig S. 2004; Rac1 and PAK1 are upstream of IKK-ϵ and TBK-1 in the viral activation of interferon regulatory factor-3. FEBS Lett 567:230–238 [CrossRef][PubMed]
    [Google Scholar]
  9. Fitzgerald K. A., McWhirter S. M., Faia K. L., Rowe D. C., Latz E., Golenbock D. T., Coyle A. J., Liao S. M., Maniatis T. 2003; IKKϵ and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 4:491–496 [CrossRef][PubMed]
    [Google Scholar]
  10. Guerrero-Plata A., Casola A., Suarez G., Yu X., Spetch L., Peeples M. E., Garofalo R. P. 2006; Differential response of dendritic cells to human metapneumovirus and respiratory syncytial virus. Am J Respir Cell Mol Biol 34:320–329 [CrossRef][PubMed]
    [Google Scholar]
  11. Hall C. B. 2001; Respiratory syncytial virus and parainfluenza virus. N Engl J Med 344:1917–1928 [CrossRef][PubMed]
    [Google Scholar]
  12. Hiscott J. 2007; Triggering the innate antiviral response through IRF-3 activation. J Biol Chem 282:15325–15329 [CrossRef][PubMed]
    [Google Scholar]
  13. Hwang S., Kim K. S., Flano E., Wu T. T., Tong L. M., Park A. N., Song M. J., Sanchez D. J., O’Connell R. M. et al. 2009; Conserved herpesviral kinase promotes viral persistence by inhibiting the IRF-3-mediated type I interferon response. Cell Host Microbe 5:166–178 [CrossRef][PubMed]
    [Google Scholar]
  14. Jin H., Zhou H., Cheng X., Tang R., Munoz M., Nguyen N. 2000; Recombinant respiratory syncytial viruses with deletions in the NS1, NS2, SH, and M2-2 genes are attenuated in vitro and in vivo. Virology 273:210–218 [CrossRef][PubMed]
    [Google Scholar]
  15. Kawai T., Akira S. 2008; Toll-like receptor and RIG-I-like receptor signaling. Ann N Y Acad Sci 1143:1–20 [CrossRef][PubMed]
    [Google Scholar]
  16. Lefort S., Soucy-Faulkner A., Grandvaux N., Flamand L. 2007; Binding of Kaposi’s sarcoma-associated herpesvirus K-bZIP to interferon-responsive factor 3 elements modulates antiviral gene expression. J Virol 81:10950–10960 [CrossRef][PubMed]
    [Google Scholar]
  17. 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]
    [Google Scholar]
  18. Lin R., Genin P., Mamane Y., Sgarbanti M., Battistini A., Harrington W. J. Jr, Barber G. N., Hiscott J. 2001; HHV-8 encoded vIRF-1 represses the interferon antiviral response by blocking IRF-3 recruitment of the CBP/p300 coactivators. Oncogene 20:800–811 [CrossRef][PubMed]
    [Google Scholar]
  19. Ling Z., Tran K. C., Teng M. N. 2009; Human respiratory syncytial virus nonstructural protein NS2 antagonizes the activation of beta interferon transcription by interacting with RIG-I. J Virol 83:3734–3742 [CrossRef][PubMed]
    [Google Scholar]
  20. Liu P., Jamaluddin M., Li K., Garofalo R. P., Casola A., Brasier A. R. 2007; Retinoic acid-inducible gene I mediates early antiviral response and Toll-like receptor 3 expression in respiratory syncytial virus-infected airway epithelial cells. J Virol 81:1401–1411 [CrossRef][PubMed]
    [Google Scholar]
  21. Munday D. C., Emmott E., Surtees R., Lardeau C. H., Wu W., Duprex W. P., Dove B. K., Barr J. N., Hiscox J. A. 2010; Quantitative proteomic analysis of A549 cells infected with human respiratory syncytial virus. Mol Cell Proteomics 9:2438–2459 [CrossRef][PubMed]
    [Google Scholar]
  22. Servant M. J., ten Oever B., LePage C., Conti L., Gessani S., Julkunen I., Lin R., Hiscott J. 2001; Identification of distinct signaling pathways leading to the phosphorylation of interferon regulatory factor 3. J Biol Chem 276:355–363 [CrossRef][PubMed]
    [Google Scholar]
  23. Spann K. M., Tran K. C., Chi B., Rabin R. L., Collins P. L. 2004; Suppression of the induction of alpha, beta, and lambda interferons by the NS1 and NS2 proteins of human respiratory syncytial virus in human epithelial cells and macrophages. J Virol 78:4363–4369 [CrossRef][PubMed]
    [Google Scholar]
  24. Spann K. M., Tran K. C., Collins P. L. 2005; Effects of nonstructural proteins NS1 and NS2 of human respiratory syncytial virus on interferon regulatory factor 3, NF-κB, and proinflammatory cytokines. J Virol 79:5353–5362 [CrossRef][PubMed]
    [Google Scholar]
  25. Suhara W., Yoneyama M., Kitabayashi I., Fujita T. 2002; Direct involvement of CREB-binding protein/p300 in sequence-specific DNA binding of virus-activated interferon regulatory factor-3 holocomplex. J Biol Chem 277:22304–22313 [CrossRef][PubMed]
    [Google Scholar]
  26. Swedan S., Musiyenko A., Barik S. 2009; Respiratory syncytial virus nonstructural proteins decrease levels of multiple members of the cellular interferon pathways. J Virol 83:9682–9693 [CrossRef][PubMed]
    [Google Scholar]
  27. Taniguchi T., Ogasawara K., Takaoka A., Tanaka N. 2001; IRF family of transcription factors as regulators of host defense. Annu Rev Immunol 19:623–655 [CrossRef][PubMed]
    [Google Scholar]
  28. Teng M. N., Collins P. L. 1999; Altered growth characteristics of recombinant respiratory syncytial viruses which do not produce NS2 protein. J Virol 73:466–473[PubMed]
    [Google Scholar]
  29. Wagoner J., Austin M., Green J., Imaizumi T., Casola A., Brasier A., Khabar K. S., Wakita T., Gale M. Jr, Polyak S. J. 2007; Regulation of CXCL-8 (interleukin-8) induction by double-stranded RNA signaling pathways during hepatitis C virus infection. J Virol 81:309–318 [CrossRef][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.032987-0
Loading
/content/journal/jgv/10.1099/vir.0.032987-0
Loading

Data & Media loading...

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error