Suppression of a pro-apoptotic K+ channel as a mechanism for hepatitis C virus persistence.
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.
Mankouri
Jamel
J
Institute of Molecular and Cellular Biology, Faculty of Biological Sciences and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom.
Dallas
Mark L
ML
Hughes
Mair E
ME
Griffin
Stephen D C
SD
Macdonald
Andrew
A
Peers
Chris
C
Harris
Mark
M
D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D004220:Disulfides / Q000494:pharmacology; D016174:Hepacivirus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000378:metabolism / Q000821:virology; D006801:Humans; D018384:Oxidative Stress; D051669:Shab Potassium Channels / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
D015082:2,2'-Dipyridyl; D004220:Disulfides; D051669:Shab Potassium Channels; D017361:Viral Nonstructural Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C496988:KCNB1 protein, human; C001105:2,2'-dipyridyl disulfide; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase