Interaction between the HCV NS3 protein and the host TBK1 protein leads to inhibition of cellular antiviral responses

Hepatology. 2005 May;41(5):1004-12. doi: 10.1002/hep.20666.

Abstract

The persistent nature of hepatitis C virus (HCV) infection suggests that HCV encodes proteins that enable it to overcome host antiviral responses. Toll-like receptor 3 (TLR3)-mediated signaling, which recognizes the double-stranded RNA that is produced during viral replication and induces type I interferons, including interferon beta (IFN-beta), is crucial to the host defense against viruses. Recent studies suggest that a TIR domain-containing adaptor protein, TRIF, and two protein kinases, TANK-binding kinase-1 (TBK1) and IkappaB kinase-epsilon (IKKepsilon), play essential roles in TLR3-mediated IFN-beta production through the activation of the transcriptional factor interferon regulatory factor 3 (IRF-3). We report that the HCV NS3 protein interacts directly with TBK1, and that this binding results in the inhibition of the association between TBK1 and IRF-3, which leads to the inhibition of IRF-3 activation. In conclusion, these results suggest the mechanisms of the inhibition of the innate immune responses of HCV infection by NS3 protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / metabolism
  • Binding, Competitive
  • Cell Line
  • DNA-Binding Proteins / metabolism
  • Hepacivirus / genetics
  • Hepacivirus / growth & development*
  • Hepatitis C / immunology*
  • Hepatitis C / metabolism*
  • Humans
  • Interferon Regulatory Factor-3
  • Interferons / genetics
  • Interferons / pharmacology
  • Kidney / cytology
  • Promoter Regions, Genetic / physiology
  • Protein-Serine-Threonine Kinases / metabolism*
  • Replicon / genetics
  • Signal Transduction
  • Transcription Factors / metabolism
  • Viral Nonstructural Proteins / metabolism*
  • Virus Replication / drug effects
  • Virus Replication / physiology

Substances

  • Adaptor Proteins, Vesicular Transport
  • DNA-Binding Proteins
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • NS3 protein, hepatitis C virus
  • TICAM1 protein, human
  • Transcription Factors
  • Viral Nonstructural Proteins
  • Interferons
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human