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

被引:63
作者
Prikhod'ko, EA
Prikhod'ko, GG
Siegel, RM
Thompson, P
Major, ME
Cohen, JI
机构
[1] NIAID, Med Virol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA
[2] Amer Red Cross, Holland Lab, Plasma Derivatives Dept, Rockville, MD 20855 USA
[3] NIAID, Mol Dev Immune Syst Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA
[4] US FDA, Lab Hepatitis Res, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA
关键词
hepatitis C virus; apoptosis; caspase-8; flavivirus;
D O I
10.1016/j.virol.2004.08.012
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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. Published by Elsevier Inc.
引用
收藏
页码:53 / 67
页数:15
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