Inhibition of dsRNA-induced signaling in hepatitis C virus-infected cells by NS3 protease-dependent and -independent mechanisms
Inhibition of dsRNA-induced signaling in hepatitis C virus-infected cells by NS3 protease-dependent and -independent mechanisms
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DOI：
10.1073/pnas.0602957103
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发表时间：
2006-05-30
影响因子：
11.1
通讯作者：
Chisari, Francis V.
中科院分区：
文献类型：
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作者：
Cheng, Guofeng;Zhong, Jin;Chisari, Francis V.
最近建立了强大的丙型肝炎病毒（HCV）细胞培养系统，可以分析HCV感染期间病毒与宿主的相互作用。在这里，我们报告说，HCV基因型2a（JFH-1）感染未能诱导IFN-β或IFN-刺激的基因表达的Huh-7细胞，它阻断IFN-β和IFN-刺激的基因的合成dsRNA转染后的生产。HCV感染和未感染细胞中dsRNA信号通路的单个组分的过表达表明，HCV通过使线粒体抗病毒信号蛋白/IFN-β启动子刺激因子1（MAVS/IPS-1）失活来抑制IFN-β启动子活性，同时使IFN诱导的Janus激酶信号转导和转录激活因子（JAK-STAT）信号通路保持完整。我们还表明，HCV感染细胞中MAVS/IPS-1依赖性IFN-β启动子活性完全恢复的非结构蛋白3（NS 3）蛋白酶抑制剂BILN 20611。相反，合成dsRNA诱导的IFN-β启动子活性不被BILN 2061恢复，尽管它被RIG-I的过表达部分恢复。这些结果支持了最近报道的证据，即HCV NS 3蛋白酶通过蛋白水解切割MAVS/IPS-1来减弱HCV诱导IFN-β启动子活性的能力。结果还表明，HCV阻断合成dsRNA诱导的信号通路在一个点上游的MAVS/IPS-1，它这样做的NS 3-独立的机制。
The recent establishment of a robust hepatitis C virus (HCV) cell culture system permits analysis of virus-host interactions during HCV infection. Here, we report that HCV genotype 2a (JFH-1) infection fails to induce IFN-beta or IFN-stimulated gene expression in Huh-7 cells, and that it blocks IFN-beta and IFN-stimulated gene production after transfection of synthetic dsRNA. Overexpression of individual components of the dsRNA-signaling pathway in HCV-infected and uninfected cells indicates that HCV inhibits IFN-beta promoter activity by inactivating the mitochondrial antiviral signaling protein/IFN-beta promoter stimulator 1 (MAVS/IPS-1), while leaving the IFN-induced Janus kinases-signal transducers and activators of transcription (JAK-STAT) signaling pathway intact. We also show that MAVS/IPS-1-dependent IFN-beta promoter activity in HCV-infected cells is fully restored by the nonstructural protein 3 (NS3) protease inhibitor BILN20611. In contrast, synthetic dsRNA-induced IFN-beta promoter activity is not restored by BILN2061, although it is partially restored by overexpression of RIG-I. These results support recently reported evidence that the HCV NS3 protease blunts the ability of HCV to induce IFN-beta promoter activity by proteolytically cleaving MAVS/IPS-1. The results also suggest that HCV blocks the synthetic dsRNA-induced signaling pathway at a point upstream of MAVS/IPS-1, and that it does so by an NS3-independent mechanism.