Hepatitis C virus infection activates an innate pathway involving IKK-? in lipogenesis and viral assembly.

ABSTRACT: Hepatitis C virus (HCV) interacts extensively with host factors to not only establish productive infection but also trigger unique pathological processes. Our recent genome-wide siRNA screen demonstrated that I?B kinase-? (IKK-?) is a crucial host factor for HCV. Here we describe a new nuclear factor ?B (NF-?B)-independent and kinase-mediated nuclear function of IKK-? in HCV assembly. HCV, through its 3' untranslated region, interacts with DEAD box polypeptide 3, X-linked (DDX3X) to activate IKK-?, which translocates to the nucleus and induces a CBP/p300-mediated transcriptional program involving sterol regulatory element-binding proteins (SREBPs). This innate pathway induces lipogenic genes and enhances core-associated lipid droplet formation to facilitate viral assembly. Chemical inhibitors of IKK-? suppress HCV infection and IKK-?-induced lipogenesis, offering a proof-of-concept approach for new HCV therapeutic development. Our results show that HCV uses a novel mechanism to exploit intrinsic innate responses and hijack lipid metabolism, which may contribute to high chronicity rates and the pathological hallmark of steatosis in HCV infection.

SUBMITTER: Li Q 

PROVIDER: S-EPMC3676727 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature