Eukaryotic translation initiation factor 4AII contributes to microRNA-122 regulation of hepatitis C virus replication.
Eukaryotic translation initiation factor 4AII contributes to microRNA-122 regulation of hepatitis C virus replication.
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DOI：
10.1093/nar/gky262
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发表时间：
2018-07-06
影响因子：
14.9
通讯作者：
Jopling CL
中科院分区：
文献类型：
--
作者：
Ahmed CS;Winlow PL;Parsons AL;Jopling CL
丙型肝炎病毒（HCV）是一种持续感染人类肝脏的正义RNA病毒，可导致肝硬化和肝细胞癌。HCV复制需要肝脏特异性microRNA-122（miR-122）。与典型的miRNA通过3′UTR位点介导的抑制相反，miR-122通过与病毒RNA的5′非翻译区（UTR）直接相互作用来正向调节HCV复制。这种不寻常的miRNA调控的蛋白质因子要求仍然知之甚少。在这里，我们确定了eIF 4AII，以前参与通过3′UTR位点的miRNA介导的抑制，作为一个主机因子，是HCV复制的重要。我们证明了eIF 4AII与HCV RNA相互作用，并且这种相互作用是miR-122依赖的。我们表明，有效的miR-122结合，并调节，HCV RNA减少后eIF 4AII耗尽。我们发现，先前鉴定的HCV辅因子hocT 1也参与了通过3′UTR位点的miRNA介导的抑制，有助于通过eIF 4AII调节HCV。最后，我们发现eIF 4AI敲除可抑制由eIF 4AII或hocT 1缺失介导的HCV复制。我们的研究结果表明eIF 4A蛋白之间的竞争效应通过调节miR-122功能来影响HCV复制。
Hepatitis C virus (HCV) is a positive sense RNA virus that persistently infects human liver, leading to cirrhosis and hepatocellular carcinoma. HCV replication requires the liver-specific microRNA-122 (miR-122). In contrast to canonical miRNA-mediated repression via 3′UTR sites, miR-122 positively regulates HCV replication by a direct interaction with the 5′ untranslated region (UTR) of the viral RNA. The protein factor requirements for this unusual miRNA regulation remain poorly understood. Here, we identify eIF4AII, previously implicated in miRNA-mediated repression via 3′UTR sites, as a host factor that is important for HCV replication. We demonstrate that eIF4AII interacts with HCV RNA and that this interaction is miR-122-dependent. We show that effective miR-122 binding to, and regulation of, HCV RNA are reduced following eIF4AII depletion. We find that the previously identified HCV co-factor CNOT1, which has also been implicated in miRNA-mediated repression via 3′UTR sites, contributes to regulation of HCV by eIF4AII. Finally, we show that eIF4AI knockdown alleviates the inhibition of HCV replication mediated by depletion of either eIF4AII or CNOT1. Our results suggest a competition effect between the eIF4A proteins to influence HCV replication by modulation of miR-122 function.
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