title: Hepatitis C virus infection activates an innate pathway involving IKK-α 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 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.
authors.affiliation: Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Qisheng
authors.initials: Q
authors.lastname: Li
authors.forename: Véronique
authors.initials: V
authors.lastname: Pène
authors.forename: Siddharth
authors.initials: S
authors.lastname: Krishnamurthy
authors.forename: Helen
authors.initials: H
authors.lastname: Cha
authors.forename: T Jake
authors.initials: TJ
authors.lastname: Liang
mesh_terms: D020413:3' Untranslated Regions; D021581:Active Transport, Cell Nucleus; D053487:DEAD-box RNA Helicases / Q000502:physiology; D006526:Hepatitis C / Q000378:metabolism* / Q000821:virology; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology*; D050155:Lipogenesis; D016328:NF-kappa B / Q000502:physiology; D010766:Phosphorylation; D015398:Signal Transduction; D051779:Sterol Regulatory Element Binding Proteins / Q000502:physiology; D019065:Virus Assembly; D050880:p300-CBP Transcription Factors / Q000502:physiology
chemical_list: D020413:3' Untranslated Regions; D016328:NF-kappa B; D051779:Sterol Regulatory Element Binding Proteins; D050880:p300-CBP Transcription Factors; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases