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 IjB kinase-a (IKK-a) is a crucial host factor for HCV. Here we describe a new nuclear factor jB (NF-jB)-independent and kinase-mediated nuclear function of IKK-a in HCVassembly. HCV, through its 3' untranslated region, interacts with DEAD box polypeptide 3, X-linked (DDX3X) to activate IKK-a, 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-a suppress HCV infection and IKK-a-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.
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