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 Mannová, P.
Right arrow Articles by Beretta, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mannová, P.
Right arrow Articles by Beretta, L.

 Previous Article  |  Next Article 

Journal of Virology, July 2005, p. 8742-8749, Vol. 79, No. 14
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.14.8742-8749.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Activation of the N-Ras–PI3K–Akt-mTOR Pathway by Hepatitis C Virus: Control of Cell Survival and Viral Replication

Petra Mannová and Laura Beretta*

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109

Received 16 November 2004/ Accepted 16 March 2005

The hepatitis C virus (HCV) replication complex is localized within detergent-resistant membranes or lipid rafts. We analyzed the protein contents of detergent-resistant fractions isolated from Huh7 cells expressing a self-replicating full-length HCV-1b genome. Using two-dimensional gel electrophoresis followed by mass spectrometry, we identified N-Ras as one of the proteins in which expression was increased in the detergent-resistant fractions from HCV genomic replicon clones compared to control cells. N-Ras is an activator of the phosphatidylinositol-3-kinase (PI3K)-Akt pathway. We found that the activities of PI3K and Akt, as well as the activity of their downstream target, mTOR, in the HCV-replicating cells were increased. Both PI3K-Akt- and mTOR-dependent pathways have been shown to promote cell survival. In agreement with this, HCV replicon cells were resistant to serum starvation-induced apoptosis. We also characterized the role of this pathway in HCV replication. Reduction of N-Ras expression by transfection of N-Ras small interfering RNA (siRNA) resulted in increased replication of HCV. We observed a similar increase in HCV replication in cells treated with the PI3K inhibitor LY294002 and in cells transfected with mTOR siRNA. Taken together, these data suggest that increased N-Ras levels in subcellular sites of HCV replication and stimulation of the prosurvival PI3K-Akt pathway and mTOR by HCV not only protect cells against apoptosis but also contribute to the maintenance of steady-state levels of HCV replication. These effects may contribute to the establishment of persistent infection by HCV.


* Corresponding author. Mailing address: Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. North, M5-A864, Box 19024, Seattle, WA 98109-1024. Phone: (206) 667-7080. Fax: (206) 667-2537. E-mail: lberetta{at}fhcrc.org.


Journal of Virology, July 2005, p. 8742-8749, Vol. 79, No. 14
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.14.8742-8749.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.




This article has been cited by other articles:

  • Rogers, P. M., Mashtalir, N., Rathod, M. A., Dubuisson, O., Wang, Z., Dasuri, K., Babin, S., Gupta, A., Markward, N., Cefalu, W. T., Dhurandhar, N. V. (2008). Metabolically Favorable Remodeling of Human Adipose Tissue by Human Adenovirus Type 36. Diabetes 57: 2321-2331 [Abstract] [Full Text]  
  • Guo, H., Zhou, T., Jiang, D., Cuconati, A., Xiao, G.-H., Block, T. M., Guo, J.-T. (2007). Regulation of Hepatitis B Virus Replication by the Phosphatidylinositol 3-Kinase-Akt Signal Transduction Pathway. J. Virol. 81: 10072-10080 [Abstract] [Full Text]  
  • Stone, M., Jia, S., Heo, W. D., Meyer, T., Konan, K. V. (2007). Participation of Rab5, an Early Endosome Protein, in Hepatitis C Virus RNA Replication Machinery. J. Virol. 81: 4551-4563 [Abstract] [Full Text]  
  • Ishida, H., Li, K., Yi, M., Lemon, S. M. (2007). p21-activated Kinase 1 Is Activated through the Mammalian Target of Rapamycin/p70 S6 Kinase Pathway and Regulates the Replication of Hepatitis C Virus in Human Hepatoma Cells. J. Biol. Chem. 282: 11836-11848 [Abstract] [Full Text]  
  • Shin, Y.-K., Liu, Q., Tikoo, S. K., Babiuk, L. A., Zhou, Y. (2007). Effect of the phosphatidylinositol 3-kinase/Akt pathway on influenza A virus propagation. J. Gen. Virol. 88: 942-950 [Abstract] [Full Text]  
  • Mannova, P., Fang, R., Wang, H., Deng, B., McIntosh, M. W., Hanash, S. M., Beretta, L. (2006). Modification of Host Lipid Raft Proteome upon Hepatitis C Virus Replication. Mol. Cell. Proteomics 5: 2319-2325 [Abstract] [Full Text]  
  • Benetti, L., Roizman, B. (2006). Protein Kinase B/Akt Is Present in Activated Form throughout the Entire Replicative Cycle of {Delta}US3 Mutant Virus but Only at Early Times after Infection with Wild-Type Herpes Simplex Virus 1.. J. Virol. 80: 3341-3348 [Abstract] [Full Text]  
  • Wang, G., Barrett, J. W., Stanford, M., Werden, S. J., Johnston, J. B., Gao, X., Sun, M., Cheng, J. Q., McFadden, G. (2006). Infection of human cancer cells with myxoma virus requires Akt activation via interaction with a viral ankyrin-repeat host range factor. Proc. Natl. Acad. Sci. USA 103: 4640-4645 [Abstract] [Full Text]  
  • Liu, W. J., Wang, X. J., Clark, D. C., Lobigs, M., Hall, R. A., Khromykh, A. A. (2006). A Single Amino Acid Substitution in the West Nile Virus Nonstructural Protein NS2A Disables Its Ability To Inhibit Alpha/Beta Interferon Induction and Attenuates Virus Virulence in Mice. J. Virol. 80: 2396-2404 [Abstract] [Full Text]  
  • Lee, S. H., Kim, Y. K., Kim, C. S., Seol, S. K., Kim, J., Cho, S., Song, Y. L., Bartenschlager, R., Jang, S. K. (2005). E2 of Hepatitis C Virus Inhibits Apoptosis. J. Immunol. 175: 8226-8235 [Abstract] [Full Text]