Viral and therapeutic control of IFN-β promoter stimulator 1 during hepatitis C virus infection
Viral and therapeutic control of IFN-β promoter stimulator 1 during hepatitis C virus infection
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DOI：
10.1073/pnas.0601523103
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发表时间：
2006-04-11
影响因子：
11.1
通讯作者：
Gale, M
中科院分区：
文献类型：
--
作者：
Loo, YM;Owen, DM;Gale, M
通过视黄酸诱导基因-I（RIG-I）及其衔接蛋白IFN启动子-刺激因子1（IPS-1）的病毒信号传导激活IFN调节因子-3（IRF-3）和限制病毒感染的宿主IFN-α/β应答。丙型肝炎病毒（HCV）NS 3/4A蛋白酶切割IPS-1以阻断RIG-I信号传导，但这种调节如何控制宿主对HCV的反应尚不清楚。此外，内源性IPS-1切割尚未在体外或体内HCV感染的背景下得到证实。在这里，我们表明，HCV感染瞬时诱导RIG-I和IPS-1依赖的IRF-3激活。这种宿主反应限制了HCV的产生，并限制了细胞对感染的容许性。然而，HCV在感染早期通过NS 3/4A在C508处切割IPS-1，从线粒体膜释放IPS-1来破坏这种应答。切割导致IPS-1的亚细胞再分布和与RIG-I相互作用的丧失，从而阻止下游IRF-3活化和IFN-β诱导。来自慢性感染患者的肝组织类似地证明了IPS-1在感染肝细胞中的亚细胞再分布以及与体内缺乏ISG 15表达和靶蛋白缀合相关的IPS-1切割。重要的是，NS 3/4A的小分子抑制剂防止切割并恢复IFN-β诱导的RIG-I信号传导。我们的研究结果表明，在一个动态模型中，早期激活的IRF-3和诱导的抗病毒基因逆转IPS-1蛋白水解和废除的RIG-I信号作为NS 3/4A积累在新感染的细胞。HCV蛋白酶抑制剂有效地防止IPS-1蛋白水解，这表明它们可能能够在临床实践中恢复这种先天宿主反应。
Viral signaling through retinoic acid-inducible gene-I (RIG-I) and its adaptor protein, IFN promoter-stimulator 1 (IPS-1), activates IFN regulatory factor-3 (IRF-3) and the host IFN-alpha/beta response that limits virus infection. The hepatitis C virus (HCV) NS3/4A protease cleaves IPS-1 to block RIG-I signaling, but how this regulation controls the host response to HCV is not known. Moreover, endogenous IPS-1 cleavage has not been demonstrated in the context of HCV infection in vitro or in vivo. Here, we show that HCV infection transiently induces RIG-I- and IPS-1-dependent IRF-3 activation. This host response limits HCV production and constrains cellular permissiveness to infection. However, HCV disrupts this response early in infection by NS3/4A cleavage of IPS-1 at C508, releasing IPS-1 from the mitochondrial membrane. Cleavage results in subcellular redistribution of IPS-1 and loss of interaction with RIG-I, thereby preventing downstream activation of IRF-3 and IFN-beta induction. Liver tissues from chronically infected patients similarly demonstrate subcellular redistribution of IPS-1 in infected hepatocytes and IPS-1 cleavage associated with a lack of ISG15 expression and conjugation of target proteins in vivo. Importantly, small-molecule inhibitors of NS3/4A prevent cleavage and restore RIG-I signaling of IFN-beta induction. Our results suggest a dynamic model in which early activation of IRF-3 and induction of antiviral genes are reversed by IPS-1 proteolysis and abrogation of RIG-I signaling as NS3/4A accumulates in newly infected cells. HCV protease inhibitors effectively prevent IPS-1 proteolysis, suggesting they may be capable of restoring this innate host response in clinical practice.