Hepatitis C virus expression suppresses interferon signaling by degrading STAT1

Gastroenterology. 2005 Apr;128(4):1034-41. doi: 10.1053/j.gastro.2005.02.006.


Background & aims: The molecular mechanisms by which hepatitis C virus (HCV) antagonizes the antiviral actions of interferon (IFN) have not been fully characterized. Specifically, how HCV proteins impact on IFN signaling components has yet to be elucidated. We used an HCV cell-based expression model to examine the interaction between HCV protein expression and host type I IFN signaling components in the Jak-STAT kinase pathway.

Methods: Full-length HCV and HCV subgenomic constructs corresponding to structural and each of the nonstructural proteins were transiently transfected into Huh-T7 cells. HCV expression was monitored by an HCV core antigen enzyme-linked immunosorbent assay. STAT1, P-STAT1, and HCV protein expression was investigated with immunoprecipitation and Western blots.

Results: Overexpression and small interfering RNA studies showed that STAT1 was indispensable for control of HCV expression. STAT1 and P-STAT1 expression were markedly reduced in HCV-transfected cells. Full-length HCV, HCV core/E1/E2, and NS3-4A were each associated with decreased STAT1 expression, which was attributable to proteasome-dependent degradation of STAT1. HCV core, but not HCV E1, E2, NS3, NS4, or NS5, bound to STAT1. STAT2 expression was not affected by HCV.

Conclusions: HCV expression selectively degrades STAT1 and reduces P-STAT1 accumulation in the nucleus in a proteasome-dependent manner. HCV core protein binds STAT1, suggesting that this viral protein is associated with STAT1 degradation. STAT1 plays an indispensable role in innate antiviral immunity against HCV expression. In turn, HCV subverts the Jak-STAT kinase by selectively inducing STAT1 degradation.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cytoplasm / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Hepacivirus / metabolism
  • Hepacivirus / physiology*
  • Humans
  • Interferons / antagonists & inhibitors*
  • Interferons / metabolism*
  • Nuclear Proteins / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • STAT1 Transcription Factor
  • STAT2 Transcription Factor
  • Signal Transduction / physiology*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transfection
  • Viral Core Proteins / metabolism
  • Viral Proteins / physiology


  • DNA-Binding Proteins
  • Nuclear Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT2 Transcription Factor
  • STAT2 protein, human
  • Trans-Activators
  • Viral Core Proteins
  • Viral Proteins
  • Interferons
  • Proteasome Endopeptidase Complex