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Journal of Virology, May 2006, p. 4372-4379, Vol. 80, No. 9
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.9.4372-4379.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Hepatitis C Virus Core Protein Inhibits Tumor Necrosis Factor Alpha-Mediated Apoptosis by a Protective Effect Involving Cellular FLICE Inhibitory Protein

Kousuke Saito,1 Keith Meyer,1 Rebecca Warner,1 Arnab Basu,1 Ratna B. Ray,1,2 and Ranjit Ray1,3*

Departments of Internal Medicine,1 Pathology,2 Molecular Microbiology & Immunology, Saint Louis University, St. Louis, Missouri 631103

Received 1 December 2005/ Accepted 9 February 2006

We have previously shown that hepatitis C virus (HCV) core protein modulates multiple cellular processes, including those that inhibit tumor necrosis factor alpha (TNF-{alpha})-mediated apoptosis. In this study, we have investigated the signaling mechanism for inhibition of TNF-{alpha}-mediated apoptosis in human hepatoma (HepG2) cells expressing core protein alone or in context with other HCV proteins. Activation of caspase-3 and the cleavage of DNA repair enzyme poly(ADP-ribose) polymerase were inhibited upon TNF-{alpha} exposure in HCV core protein-expressing HepG2 cells. In vivo protein-protein interaction studies displayed an association between TNF receptor 1 (TNFR1) and TNFR1-associated death domain protein (TRADD), suggesting that the core protein does not perturb this interaction. A coimmunoprecipitation assay also suggested that HCV core protein does not interfere with the TRADD-Fas-associated death domain protein (FADD)-procaspase-8 interaction. Further studies indicated that HCV core protein expression inhibits caspase-8 activation by sustaining the expression of cellular FLICE (FADD-like interleukin-1ß-converting enzyme)-like inhibitory protein (c-FLIP). Similar observations were also noted upon expression of core protein in context to other HCV proteins expressed from HCV full-length plasmid DNA or a replicon. A decrease in endogenous c-FLIP by specific small interfering RNA induced TNF-{alpha}-mediated apoptotic cell death and caspase-8 activation. Taken together, our results suggested that the TNF-{alpha}-induced apoptotic pathway is inhibited by a sustained c-FLIP expression associated with the expression of HCV core protein, which may play a role in HCV-mediated pathogenesis.

* Corresponding author. Mailing address: Division of Infectious Diseases & Immunology, Saint Louis University, 3635 Vista Ave., FDT-8N, St. Louis, MO 63110. Phone: (314) 577-8648. Fax: (314) 771-3816. E-mail: rayr{at}slu.edu.

Journal of Virology, May 2006, p. 4372-4379, Vol. 80, No. 9
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.9.4372-4379.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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