Hepatitis C Virus Infection Activates a Novel Innate Pathway Involving IKK in Lipogenesis and Viral Assembly

Hepatitis C virus interacts extensively with host factors not only to establish productive infection but also to trigger unique pathological processes. Our recent genome-wide siRNA screen demonstrated that IKK is a critical host factor for HCV. Here we describe a novel NF-B-independent and kinase-mediated nuclear function of IKK in HCV assembly. HCV infection, through its 3-untranslated region, interacts with DDX3X to activate IKK, which translocates to the nucleus and induces a CBP/p300-mediated transcriptional program involving SREBPs. This novel 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 novel HCV therapeutic development. Our results show that HCV commands a novel mechanism to its advantage by exploiting intrinsic innate response and hijacking lipid metabolism, which likely contributes to a high chronicity rate and the pathological hallmark of steatosis in HCV infection.

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Li Q, Pène V, Krishnamurthy S, Cha H, Liang TJ