Influenza A virus polymerase inhibits type I interferon induction by binding to interferon beta promoter stimulator 1

J Biol Chem. 2010 Oct 15;285(42):32064-74. doi: 10.1074/jbc.M110.112458. Epub 2010 Aug 10.

Abstract

Type I interferons (IFNs) are known to be critical factors in the activation of host antiviral responses and are also important in protection from influenza A virus infection. Especially, the RIG-I- and IPS-1-mediated intracellular type I IFN-inducing pathway is essential in the activation of antiviral responses in cells infected by influenza A virus. Previously, it has been reported that influenza A virus NS1 is involved in the inhibition of this pathway. We show in this report that the influenza A virus utilizes another critical inhibitory mechanism in this pathway. In fact, the viral polymerase complex exhibited an inhibitory activity on IFNβ promoter activation mediated by RIG-I and IPS-1, and this activity was not competitive with the function of NS1. Co-immunoprecipitation analysis revealed that each polymerase subunit bound to IPS-1 in mammalian cells, and each subunit inhibited the activation of IFNβ promoter by IPS-1 independently. In addition, by a combinational expression of each polymerase subunit, IPS-1-induced activation of IFNβ promoter was more efficiently inhibited by the expression of PB2 or PB2-containing complex. Moreover, the expression of PB2 inhibited the transcription of the endogenous IFNβ gene induced after influenza A virus infection. These findings demonstrate that the viral polymerase plays an important role for regulating host anti-viral response through the binding to IPS-1 and inhibition of IFNβ production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Cell Line
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism
  • DNA-Directed RNA Polymerases / genetics
  • DNA-Directed RNA Polymerases / metabolism*
  • Humans
  • Influenza A virus / enzymology*
  • Interferon Type I / genetics
  • Interferon Type I / metabolism*
  • Interferon-beta / genetics*
  • Promoter Regions, Genetic*
  • RNA Replicase / genetics
  • RNA Replicase / metabolism*
  • Signal Transduction / physiology
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism
  • Viral Proteins / genetics
  • Viral Proteins / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • INS1 protein, influenza virus
  • Interferon Type I
  • PA protein, influenza viruses
  • PB2 protein, Influenzavirus A
  • VISA protein, human
  • Viral Nonstructural Proteins
  • Viral Proteins
  • influenza virus polymerase basic protein 1
  • Interferon-beta
  • RNA Replicase
  • DNA-Directed RNA Polymerases
  • DDX58 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases