Mankouri Jamel, Dallas Mark L, Hughes Mair E, Griffin Stephen D C, Macdonald Andrew, Peers Chris, Harris Mark
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.
Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15903-8. doi: 10.1073/pnas.0906798106. Epub 2009 Aug 26.
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.
据估计，全球3%的人口感染了丙型肝炎病毒（HCV），其中大多数人会发展为慢性肝病。与其他慢性病毒一样，持续感染的建立要求HCV感染的细胞必须对一系列促凋亡刺激具有抗性。在氧化应激反应中，由Kv2.1通道介导的外向K(+)电流的放大先于细胞凋亡的发生。我们在此表明，在感染HCV或携带HCV亚基因组复制子的人肝癌细胞中，氧化应激未能通过Kv2.1引发细胞凋亡。HCV NS5A蛋白通过抑制氧化应激诱导的Kv2.1的p38 MAPK磷酸化来介导这种效应。病毒蛋白对宿主细胞K(+)通道的抑制是一种迄今未被描述的病毒抗凋亡机制，并且是抗病毒治疗的一个潜在靶点。
