A Novel Mechanism for the Inhibition of Interferon Regulatory factor-3-dependent Gene Expression by Human Respiratory Syncytial Virus NS1 Protein

J Gen Virol. 2011 Sep;92(Pt 9):2153-2159. doi: 10.1099/vir.0.032987-0. Epub 2011 Jun 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Epithelial Cells / virology
  • Humans
  • Interferon Regulatory Factor-3 / antagonists & inhibitors*
  • Protein Binding
  • Respiratory Syncytial Virus, Human / immunology*
  • Viral Nonstructural Proteins / metabolism*
  • Virulence Factors / metabolism*

Substances

  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Viral Nonstructural Proteins
  • Virulence Factors