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Hepatitis C virus infection activates an innate pathway involving IKK-α in lipogenesis and viral assembly.
|Title||Hepatitis C virus infection activates an innate pathway involving IKK-α in lipogenesis and viral assembly.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Li Q, Pène V, Krishnamurthy S, Cha H, Liang JT|
|Date Published||2013 Jun|
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 IκB kinase-α (IKK-α) is a crucial host factor for HCV. Here we describe a new nuclear factor κB (NF-κB)-independent and kinase-mediated nuclear function of IKK-α in HCV assembly. HCV, through its 3' untranslated region, interacts with DEAD box polypeptide 3, X-linked (DDX3X) to activate IKK-α, 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-α suppress HCV infection and IKK-α-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.
|Alternate Journal||Nat. Med.|