DOI: 10.1128/jvi.80.9.4372-4379.2006. Hepatitis C Virus Core Protein Inhibits Tumor Necrosis Factor Alpha-Mediated Apoptosis by a Protective Effect Involving Cellular FLICE Inhibitory Protein

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

10.1128/jvi.80.9.4372-4379.2006

Crossref journal-article

American Society for Microbiology

Journal of Virology (235)

Abstract

ABSTRACTWe have previously shown that hepatitis C virus (HCV) core protein modulates multiple cellular processes, including those that inhibit tumor necrosis factor alpha (TNF-α)-mediated apoptosis. In this study, we have investigated the signaling mechanism for inhibition of TNF-α-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-α 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-1β-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-α-mediated apoptotic cell death and caspase-8 activation. Taken together, our results suggested that the TNF-α-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.

Bibliography

Saito, K., Meyer, K., Warner, R., Basu, A., Ray, R. B., & Ray, R. (2006). Hepatitis C Virus Core Protein Inhibits Tumor Necrosis Factor Alpha-Mediated Apoptosis by a Protective Effect Involving Cellular FLICE Inhibitory Protein. Journal of Virology, 80(9), 4372â4379.

Authors 6

Kousuke Saito (first)
Keith Meyer (additional)
Rebecca Warner (additional)
Arnab Basu (additional)
Ratna B. Ray (additional)
Ranjit Ray (additional)

References 36 Referenced 79

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Kataoka, T. 2005. The caspase-8 modulator c-FLIP. Crit. Rev. Immunol.25:3158. / Crit. Rev. Immunol. (2005)
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10.1172/JCI118287
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Large, M. K., D. J. Kittlesen, and Y. S. Hahn. 1999. Suppression of host immune response by the core protein of hepatitis C virus: possible implications for hepatitis C virus persistence. J. Immunol.162:931-938. (10.4049/jimmunol.162.2.931) / J. Immunol. (1999)
Lohr, H. F., J. F. Schlaak, G. Gerken, B. Fleischer, H. P. Dienes, and K. H. Meyer zum Buschenfelde. 1994. Phenotypical analysis and cytokine release of liver-infiltrating and peripheral blood T lymphocytes from patients with chronic hepatitis of different etiology. Liver14:161-166. (10.1111/j.1600-0676.1994.tb00067.x) / Liver (1994)
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Yeh, J. H., S. C. Hsu, S. H. Han, and M. Z. Lai. 1998. Mitogen-activated protein kinase kinase antagonized fas-associated death domain protein mediated apoptosis by induced FLICE-inhibitory protein expression. J. Exp. Med.16:1795-1802. / J. Exp. Med. (1998)
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Dates

Type	When
Created	19 years, 4 months ago (April 12, 2006, 3:38 p.m.)
Deposited	1 year, 6 months ago (Feb. 3, 2024, 1:56 p.m.)
Indexed	2 months, 2 weeks ago (June 13, 2025, 6:25 p.m.)
Issued	19 years, 4 months ago (May 1, 2006)
Published	19 years, 4 months ago (May 1, 2006)
Published Print	19 years, 4 months ago (May 1, 2006)

Funders 0

None

BibTeX

@article{Saito_2006, title={Hepatitis C Virus Core Protein Inhibits Tumor Necrosis Factor Alpha-Mediated Apoptosis by a Protective Effect Involving Cellular FLICE Inhibitory Protein}, volume={80}, ISSN={1098-5514}, url={http://dx.doi.org/10.1128/jvi.80.9.4372-4379.2006}, DOI={10.1128/jvi.80.9.4372-4379.2006}, number={9}, journal={Journal of Virology}, publisher={American Society for Microbiology}, author={Saito, Kousuke and Meyer, Keith and Warner, Rebecca and Basu, Arnab and Ray, Ratna B. and Ray, Ranjit}, year={2006}, month=may, pages={4372–4379} }

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