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Virology 2004 Nov 10;329(1):53-67

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

Prikhod'ko EA, Prikhod'ko GG, Siegel RM, Thompson P, Major ME, Cohen JI

Cohen JI, NIAID, Med Virol Sect, Lab Clin Infect Dis, NIH, Bldg 10,Room 11N228m10 Ctr Dr, Bethesda, MD 20892 USA NIAID, Med Virol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA Amer Red Cross, Holland Lab, Plasma Derivatives Dept, Rockville, MD 20855 USA NIAID, Mol Dev Immune Syst Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA US FDA, Lab Hepatitis Res, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA


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.

Category: Journal Article, Peer
PubMed ID: #15476874
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2011-10-04 Entry Last Modified: 2012-08-29