Activation of protein kinase R by hepatitis C virus RNA-dependent RNA polymerase.
Activation of protein kinase R by hepatitis C virus RNA-dependent RNA polymerase.
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丙型肝炎病毒 RNA 依赖性 RNA 聚合酶激活蛋白激酶 R。
DOI：
10.1016/j.virol.2019.01.024
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发表时间：
2019
期刊：
影响因子：
3.7
通讯作者：
Wakita T.
中科院分区：
文献类型：
--
作者：
Suzuki R;Matsuda M;Shimoike T;Watashi K;Aizaki H;Kato T;Suzuki T;Muramatsu M;Wakita T.
丙型肝炎病毒（HCV）激活蛋白激酶R（PKR），通过控制新转录的mRNA的翻译来抑制干扰素（IFN）和IFN刺激基因的表达。然而，目前尚不清楚HCV如何激活PKR。为了阐明HCV感染介导的PKR活化的分子机制，我们检测了病毒蛋白对PKR活化的影响。在这里，我们发现HCV NS5B的表达强烈诱导PKR和eIF2α磷酸化，并减弱MHC I类分子的表达。与此相反，日本脑炎病毒RNA依赖的RNA聚合酶的表达不诱导PKR的磷酸化。免疫共沉淀分析表明HCV NS5B与PKR相互作用。此外，NS5B与聚合酶活性缺陷突变的表达未能磷酸化PKR，这表明RNA聚合酶活性是PKR激活所必需的。这些结果表明，HCV通过与NS5B结合激活PKR，导致I类MHC的翻译抑制，从而建立慢性感染。
Hepatitis C virus (HCV) was shown to activate protein kinase R (PKR), which inhibits expression of interferon (IFN) and IFN-stimulated genes by controlling the translation of newly transcribed mRNAs. However, it is unknown exactly how HCV activates PKR. To address the molecular mechanism(s) of PKR activation mediated by HCV infection, we examined the effects of viral proteins on PKR activation. Here, we show that expression of HCV NS5B strongly induced PKR and eIF2α phosphorylation, and attenuated MHC class I expression. In contrast, expression of Japanese encephalitis virus RNA-dependent RNA polymerase did not induce phosphorylation of PKR. Co-immunoprecipitation analyses showed that HCV NS5B interacted with PKR. Furthermore, expression of NS5B with polymerase activity-deficient mutation failed to phosphorylate PKR, suggesting that RNA polymerase activity is required for PKR activation. These results suggest that HCV activates PKR by association with NS5B, resulting in translational suppression of MHC class I to establish chronic infection.