Hepatitis C Virus NS5A Binds to the mRNA Cap-binding Eukaryotic Translation Initiation 4F (eIF4F) Complex and Up-regulates Host Translation Initiation Machinery through eIF4E-binding Protein 1 Inactivation
Hepatitis C Virus NS5A Binds to the mRNA Cap-binding Eukaryotic Translation Initiation 4F (eIF4F) Complex and Up-regulates Host Translation Initiation Machinery through eIF4E-binding Protein 1 Inactivation
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DOI：
10.1074/jbc.m111.308916
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发表时间：
2012-02-10
影响因子：
4.8
通讯作者：
Krishnan, Harinivas Harshan
中科院分区：
文献类型：
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作者：
George, Anju;Panda, Swarupa;Krishnan, Harinivas Harshan
起始是宿主蛋白质翻译的主要限速步骤，是许多病毒感染的关键靶标。慢性丙型肝炎病毒（HCV）感染导致肝细胞癌。翻译起始在许多癌症中上调，在肿瘤发生中起关键作用。mTOR是宿主蛋白质翻译的主要调节因子。尽管已知HCV非结构蛋白5A（NS 5A）对PI 3 K-AKT-mTOR的激活，但对该病毒对宿主翻译起始的调节了解不多。在这里，我们第一次表明，HCV上调宿主帽依赖的翻译机制在Huh7.5细胞通过同时激活mTORC 1和真核生物翻译起始因子4 E（eIF 4 E）的NS 5A。有趣的是，NS 5A过表达并随后过度磷酸化4 EBP 1。NS 5A通过p38 MAPK-MNK途径磷酸化eIF 4 E。HCV感染和NS 5A表达均增强eIF 4F复合物组装，这是帽依赖性翻译效率的指标。然而，HCV NS 5A没有改变全局翻译。在NS 5A-Huh 7.5细胞中，4 EBP 1磷酸化而不是S6 K1磷酸化是对雷帕霉素唯一的抗性，表明4 EBP 1的替代磷酸化机制。Ser-473而不是Thr-308的抗性，AKT对PI 3 K抑制剂的磷酸化表明NS 5A激活mTORC 2。NS 5A与eIF 4F复合物和多聚核糖体相关，表明其积极参与宿主翻译。这是第一个报告，暗示了HCV蛋白的上调宿主翻译起始装置，通过同时调节多个途径。由于mTORC 1激活和eIF 4 E磷酸化都参与了肿瘤的发生，我们认为它们同时被NS 5A激活可能对肝细胞癌的发展有重要作用。
Initiation, a major rate-limiting step of host protein translation, is a critical target in many viral infections. Chronic hepatitis C virus (HCV) infection results in hepatocellular carcinoma. Translation initiation, up-regulated in many cancers, plays a critical role in tumorigenesis. mTOR is a major regulator of host protein translation. Even though activation of PI3K-AKT-mTOR by HCV non-structural protein 5A (NS5A) is known, not much is understood about the regulation of host translation initiation by this virus. Here for the first time we show that HCV up-regulates host cap-dependent translation machinery in Huh7.5 cells through simultaneous activation of mTORC1 and eukaryotic translation initiation factor 4E (eIF4E) by NS5A. NS5A, interestingly, overexpressed and subsequently hyperphosphorylated 4EBP1. NS5A phosphorylated eIF4E through the p38 MAPK-MNK pathway. Both HCV infection and NS5A expression augmented eIF4F complex assembly, an indicator of cap-dependent translation efficiency. Global translation, however, was not altered by HCV NS5A. 4EBP1 phosphorylation, but not that of S6K1, was uniquely resistant to rapamycin in NS5A-Huh7.5 cells, indicative of an alternate phosphorylation mechanism of 4EBP1. Resistance of Ser-473, but not Thr-308, phosphorylation of AKT to PI3K inhibitors suggested an activation of mTORC2 by NS5A. NS5A associated with eIF4F complex and polysomes, suggesting its active involvement in host translation. This is the first report that implicates an HCV protein in the up-regulation of host translation initiation apparatus through concomitant regulation of multiple pathways. Because both mTORC1 activation and eIF4E phosphorylation are involved in tumorigenesis, we propose that their simultaneous activation by NS5A might contribute significantly to the development of hepatocellular carcinoma.