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  • Title: The NS3 protein of hepatitis C virus induces caspase-8-mediated apoptosis independent of its protease or helicase activities.
    Author: Prikhod'ko EA, Prikhod'ko GG, Siegel RM, Thompson P, Major ME, Cohen JI.
    Journal: Virology; 2004 Nov 10; 329(1):53-67. PubMed ID: 15476874.
    Abstract:
    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.
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