The NS3 protein of hepatitis C virus induces caspase-8-mediated apoptosis independent of its protease or helicase activities

Virology. 2004 Nov 10;329(1):53-67. doi: 10.1016/j.virol.2004.08.012.


Apoptosis has been implicated in the pathogenesis of hepatitis C virus (HCV)-related disease. Here, we show that expression of HCV NS3, or the NS2/NS3 precursor protein, in mammalian cells results in induction of apoptosis and activation of caspases. HCV NS3-induced apoptosis was blocked by a caspase-8, but not a caspase-9-specific inhibitor. HCV NS3 coimmunoprecipitated with caspase-8, but not with other caspases or with FADD. Coexpression of HCV NS3 and caspase-8 resulted in aggregation of the caspase in punctate structures that colocalized with HCV NS3. Cell lines stably expressing low levels HCV NS3 showed increased sensitivity to Fas-induced cell death. Point mutations of NS3 showed that the pro-apoptotic function of the protein is distinct from its protease and helicase activities. These findings suggest that HCV NS3 promotes caspase-8 induced apoptosis at a pathway site distal to FADD, and that flavivirus NS3 may represent a new class of pro-apoptotic proteins.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis*
  • Caspase 8
  • Caspases / metabolism*
  • Cell Line
  • Chlorocebus aethiops
  • DNA Helicases / metabolism
  • Enzyme Activation
  • Hepacivirus / metabolism
  • Hepacivirus / pathogenicity*
  • Humans
  • Molecular Sequence Data
  • Peptide Hydrolases / metabolism
  • RNA Helicases / metabolism
  • Sequence Analysis, DNA
  • Vero Cells
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism
  • Viral Nonstructural Proteins / physiology*


  • NS3 protein, hepatitis C virus
  • Viral Nonstructural Proteins
  • Peptide Hydrolases
  • CASP8 protein, human
  • Caspase 8
  • Caspases
  • DNA Helicases
  • RNA Helicases