Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

PNAS 106 (37): 15903-15908

Copyright © 2009 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / MICROBIOLOGY

Suppression of a pro-apoptotic K+ channel as a mechanism for hepatitis C virus persistence

Jamel Mankouria,1, Mark L. Dallasb,1, Mair E. Hughesa, Stephen D. C. Griffina, Andrew Macdonalda, Chris Peersb, and Mark Harrisa,2

aInstitute of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Centre for Structural Molecular Biology, and bDivision of Cardiovascular and Neuronal Remodeling, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, United Kingdom

Edited by Francis V. Chisari, The Scripps Research Institute, La Jolla, CA, and approved July 16, 2009

Received for publication June 19, 2009.

Abstract: An estimated 3% of the global population are infected with hepatitis C virus (HCV), and the majority of these individuals will develop chronic liver disease. As with other chronic viruses, establishment of persistent infection requires that HCV-infected cells must be refractory to a range of pro-apoptotic stimuli. In response to oxidative stress, amplification of an outward K+ current mediated by the Kv2.1 channel, precedes the onset of apoptosis. We show here that in human hepatoma cells either infected with HCV or harboring an HCV subgenomic replicon, oxidative stress failed to initiate apoptosis via Kv2.1. The HCV NS5A protein mediated this effect by inhibiting oxidative stress-induced p38 MAPK phosphorylation of Kv2.1. The inhibition of a host cell K+ channel by a viral protein is a hitherto undescribed viral anti-apoptotic mechanism and represents a potential target for antiviral therapy.

Key Words: apoptosis • Kv2.1 • NS5A • oxidative stress

Author contributions: J.M., M.L.D., A.M., C.P., and M.H. designed research; J.M., M.L.D., M.E.H., and S.D.C.G. performed research; A.M. contributed new reagents/analytic tools; J.M., M.L.D., S.D.C.G., A.M., C.P., and M.H. analyzed data; and J.M., M.L.D., S.D.C.G., C.P., and M.H. wrote the paper.

1J.M. and M.L.D. contributed equally to this work.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0906798106/DCSupplemental.

2To whom correspondence should be addressed. E-mail: m.harris{at}leeds.ac.uk

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Metabolomic Analysis of Key Regulatory Metabolites in Hepatitis C Virus-infected Tree Shrews.
H. Sun, A. Zhang, G. Yan, C. Piao, W. Li, C. Sun, X. Wu, X. Li, Y. Chen, and X. Wang (2013)
Mol. Cell. Proteomics 12, 710-719
   Abstract »    Full Text »    PDF »
Regulation of Neuronal Proapoptotic Potassium Currents by the Hepatitis C Virus Nonstructural Protein 5A.
C. A. Norris, K. He, M. G. Springer, K. A. Hartnett, J. P. Horn, and E. Aizenman (2012)
J. Neurosci. 32, 8865-8870
   Abstract »    Full Text »    PDF »
Toxic Role of K+ Channel Oxidation in Mammalian Brain.
D. Cotella, B. Hernandez-Enriquez, X. Wu, R. Li, Z. Pan, J. Leveille, C. D. Link, S. Oddo, and F. Sesti (2012)
J. Neurosci. 32, 4133-4144
   Abstract »    Full Text »    PDF »
Dengue Virus Capsid Protein Binding to Hepatic Lipid Droplets (LD) Is Potassium Ion Dependent and Is Mediated by LD Surface Proteins.
F. A. Carvalho, F. A. Carneiro, I. C. Martins, I. Assuncao-Miranda, A. F. Faustino, R. M. Pereira, P. T. Bozza, M. A. R. B. Castanho, R. Mohana-Borges, A. T. Da Poian, et al. (2012)
J. Virol. 86, 2096-2108
   Abstract »    Full Text »    PDF »
Hepatitis C Virus NS5A Activates the Mammalian Target of Rapamycin (mTOR) Pathway, Contributing to Cell Survival by Disrupting the Interaction between FK506-binding Protein 38 (FKBP38) and mTOR.
L. Peng, D. Liang, W. Tong, J. Li, and Z. Yuan (2010)
J. Biol. Chem. 285, 20870-20881
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882