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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Inhibition of dsRNA-induced signaling in hepatitis C virus-infected cells by NS3 protease-dependent and -independent mechanisms
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Inhibition of dsRNA-induced signaling in hepatitis C virus-infected cells by NS3 protease-dependent and -independent mechanisms

机译：NS3蛋白酶依赖性和非依赖性机制抑制dsRNA诱导的丙型肝炎病毒感染细胞信号转导

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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-β or IFN-stimulated gene expression in Huh-7 cells, and that it blocks IFN-β 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-β promoter activity by inactivating the mitochondrial antiviral signaling protein/IFN-β 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-β promoter activity in HCV-infected cells is fully restored by the nonstructural protein 3 (NS3) protease inhibitor BILN2061. In contrast, synthetic dsRNA-induced IFN-β 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-β 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.
机译：健壮的丙型肝炎病毒（HCV）细胞培养系统的最新建立允许在HCV感染期间分析病毒与宿主的相互作用。在这里，我们报道HCV基因型2a（JFH-1）感染未能在Huh-7细胞中诱导IFN-β或IFN刺激的基因表达，并且它在合成dsRNA转染后阻断IFN-β和IFN刺激的基因产生。 。在HCV感染和未感染的细胞中dsRNA信号通路的各个成分的过表达表明HCV通过使线粒体抗病毒信号蛋白/IFN-β启动子刺激物1（MAVS / IPS-1）失活来抑制IFN-β启动子活性。 IFN诱导的Janus激酶信号转导和转录激活因子（JAK-STAT）信号通路完整无缺。我们还显示非结构蛋白3（NS3）蛋白酶抑制剂BILN2061完全恢复了HCV感染细胞中MAVS / IPS-1依赖性IFN-β启动子的活性。相反，合成的dsRNA诱导的IFN-β启动子活性不能被BILN2061恢复，尽管它可以通过RIG-Ⅰ的过表达而部分恢复。这些结果支持最近报道的证据，即HCV NS3蛋白酶通过蛋白水解切割MAVS / IPS-1减弱了HCV诱导IFN-β启动子活性的能力。结果还表明，HCV在MAVS / IPS-1上游的某个位置阻断了合成的dsRNA诱导的信号传导途径，并且它是通过NS3独立机制阻断的。

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