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

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