This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Saito, K.
Right arrow Articles by Ray, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Saito, K.
Right arrow Articles by Ray, R.

 Previous Article  |  Next Article 

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.



This article has been cited by other articles:

  • Mohd-Ismail, N. K., Deng, L., Sukumaran, S. K., Yu, V. C., Hotta, H., Tan, Y.-J. (2009). The Hepatitis C Virus Core Protein Contains a BH3 Domain That Regulates Apoptosis through Specific Interaction with Human Mcl-1. J. Virol. 83: 9993-10006 [Abstract] [Full Text]  
  • Poenisch, M., Burger, N., Staeheli, P., Bauer, G., Schneider, U. (2009). Protein X of Borna Disease Virus Inhibits Apoptosis and Promotes Viral Persistence in the Central Nervous Systems of Newborn-Infected Rats. J. Virol. 83: 4297-4307 [Abstract] [Full Text]  
  • Deng, L., Adachi, T., Kitayama, K., Bungyoku, Y., Kitazawa, S., Ishido, S., Shoji, I., Hotta, H. (2008). Hepatitis C Virus Infection Induces Apoptosis through a Bax-Triggered, Mitochondrion-Mediated, Caspase 3-Dependent Pathway. J. Virol. 82: 10375-10385 [Abstract] [Full Text]  
  • Liu, J., Enomoto, S., Lancto, C. A., Abrahamsen, M. S., Rutherford, M. S. (2008). Inhibition of Apoptosis in Cryptosporidium parvum-Infected Intestinal Epithelial Cells Is Dependent on Survivin. Infect. Immun. 76: 3784-3792 [Abstract] [Full Text]  
  • Banerjee, S., Saito, K., Ait-Goughoulte, M., Meyer, K., Ray, R. B., Ray, R. (2008). Hepatitis C Virus Core Protein Upregulates Serine Phosphorylation of Insulin Receptor Substrate-1 and Impairs the Downstream Akt/Protein Kinase B Signaling Pathway for Insulin Resistance. J. Virol. 82: 2606-2612 [Abstract] [Full Text]  
  • Won, S., Ikegami, T., Peters, C. J., Makino, S. (2007). NSm Protein of Rift Valley Fever Virus Suppresses Virus-Induced Apoptosis. J. Virol. 81: 13335-13345 [Abstract] [Full Text]  
  • Wati, S., Li, P., Burrell, C. J., Carr, J. M. (2007). Dengue Virus (DV) Replication in Monocyte-Derived Macrophages Is Not Affected by Tumor Necrosis Factor Alpha (TNF-{alpha}), and DV Infection Induces Altered Responsiveness to TNF-{alpha} Stimulation. J. Virol. 81: 10161-10171 [Abstract] [Full Text]  
  • Chiou, S.-H., Yang, Y.-P., Lin, J.-C., Hsu, C.-H., Jhang, H.-C., Yang, Y.-T., Lee, C.-H., Ho, L. L. T., Hsu, W.-M., Ku, H.-H., Chen, S.-J., Chen, S. S.-L., Chang, M. D. T., Wu, C.-W., Juan, L.-J. (2006). The Immediate Early 2 Protein of Human Cytomegalovirus (HCMV) Mediates the Apoptotic Control in HCMV Retinitis through Up-Regulation of the Cellular FLICE-Inhibitory Protein Expression. J. Immunol. 177: 6199-6206 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»