Hepatitis C virus infection activates an innate pathway involving IKK-α in lipogenesis and viral assembly.
Hepatitis C virus infection activates an innate pathway involving IKK-α in lipogenesis and viral assembly.
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丙型肝炎病毒与宿主因子广泛相互作用，不仅建立产生性感染，而且还触发独特的病理过程。我们最近的全基因组小干扰RNA筛查表明，IKKα是丙型肝炎病毒的关键宿主因子。在这里，我们描述了一个新的核功能的IKKκ在丙型肝炎病毒组装中的核功能的IKKαB不依赖于和激酶。丙型肝炎病毒感染通过其3‘非翻译区与DDX3X相互作用，激活IKKα，并将其移位到细胞核，诱导CBP/p300介导的涉及SREBPs的转录程序。这一新的先天途径诱导成脂基因，并促进核心相关脂滴的形成，以促进病毒组装。IKKα的化学抑制剂抑制丙型肝炎病毒感染和IKKα诱导的脂肪生成，为新的丙型肝炎治疗开发提供了一种概念验证方法。我们的结果表明，丙型肝炎病毒通过利用固有的先天反应和劫持脂代谢而拥有一种新的优势机制，这可能是导致丙型肝炎病毒感染的高慢性率和脂肪变性的病理标志。
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 IKKα is a critical host factor for HCV. Here we describe a novel NF-κB-independent and kinase-mediated nuclear function of IKKα in HCV assembly. HCV infection, through its 3’-untranslated region, interacts with DDX3X to activate IKKα, 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 IKKα suppress HCV infection and IKKα-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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