Inhibition of RIG-I-dependent signaling to the interferon pathway during hepatitis C virus expression and restoration of signaling by IKKε
Inhibition of RIG-I-dependent signaling to the interferon pathway during hepatitis C virus expression and restoration of signaling by IKKε
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DOI：
10.1128/jvi.79.7.3969-3978.2005
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发表时间：
2005-04-01
影响因子：
5.4
通讯作者：
Meurs, EF
中科院分区：
文献类型：
--
作者：
Breiman, A;Grandvaux, N;Meurs, EF
干扰素（IFN）是通过Toll样受体（TLR） - 依赖性和非依赖性机制引起的先天免疫反应的一个重要效应。作为其致病策略的一部分，丙型肝炎病毒（HCV）通过HCV NS3/4A蛋白酶活性干扰了先天免疫反应，并诱导IFN-β，从而抑制IRF-3的磷酸化，IRF-3是IFN响应的关键转录调节剂的磷酸化。在本研究中，我们证明了蛋白酶的抑制是通过部分抑制TLR衔接蛋白TRIF/TICAM1-依赖性途径的部分抑制，蛋白酶在非规范IKK IKK相关激酶IKK Epsilon和TBK-1的上游发生。然而，使用TRIF - / - 小鼠胚胎成纤维细胞揭示了NS3/4A也抑制IFN诱导涉及的TRIF独立途径。重要的是，我们表明NS3/4A可以强烈抑制最近描述的RIG-I蛋白激活IFN的能力，这表明RIG-I是独立于TRIF的NS3/4A敏感途径的关键因素。 HCV复制子细胞中IFN信号传导成分的表达，包括IKK Epsilon，TBK-1，TRIF和野生型RIG-I的组成性活性形式，导致IFN-BETA启动子反式激活，IKK Epsilon显示出最高效率。随后，IKK Epsilon的过表达导致对HCV复制子的正复制链和负复制链的抑制作用80％。部分恢复宿主细胞转录IFN-β的能力的部分恢复表明，IKK Epsilon表达能够绕过HCV介导的抑制并恢复先天抗病毒反应。
Interferon (IFN) is one important effector of the innate immune response, induced by different viral or bacterial components through Toll-like receptor (TLR)-dependent and -independent mechanisms. As part of its pathogenic strategy, hepatitis C virus (HCV) interferes with the innate immune response and induction of IFN-beta via the HCV NS3/4A protease activity which inhibits phosphorylation of IRF-3, a key transcriptional regulator of the IFN response. In the present study, we demonstrate that inhibition by the protease occurs upstream of the noncanonical IKK-related kinases IKK epsilon and TBK-1, which phosphorylate IRF-3, through partial inhibition of the TLR adapter protein TRIF/TICAM1 -dependent pathway. Use of TRIF-/- mouse embryo fibroblasts however revealed the presence of a TRIF-independent pathway involved in IFN induction that was also inhibited by NS3/4A. Importantly, we show that NS3/4A can strongly inhibit the ability of the recently described RIG-I protein to activate IFN, suggesting that RIG-I is a key factor in the TRIF-independent, NS3/4A-sensitive pathway. Expression of IFN signaling components including IKK epsilon, TBK-1, TRIF, and wild type or constitutively active forms of RIG-I in the HCV replicon cells resulted in IFN-beta promoter transactivation, with IKK epsilon displaying the highest efficiency. Subsequently, overexpression of IKK epsilon resulted in 80% inhibition of both the positive and negative replicative strands of the HCV replicon. The partial restoration of the capacity of the host cell to transcribe IFN-beta indicates that IKK epsilon expression is able to bypass the HCV-mediated inhibition and restore the innate antiviral response.