Norovirus translation requires an interaction between the C Terminus of the genome-linked viral protein VPg and eukaryotic translation initiation factor 4G.
Norovirus translation requires an interaction between the C Terminus of the genome-linked viral protein VPg and eukaryotic translation initiation factor 4G.
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DOI：
10.1074/jbc.m114.550657
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发表时间：
2014-08-01
期刊：
影响因子：
--
通讯作者：
Goodfellow IG
中科院分区：
文献类型：
--
作者：
Chung L;Bailey D;Leen EN;Emmott EP;Chaudhry Y;Roberts LO;Curry S;Locker N;Goodfellow IG
背景：诺如病毒使用病毒编码的蛋白VPg与病毒RNA共价连接进行翻译。结果：VPg与eIF 4G的中心结构域直接相互作用是诺如病毒翻译所必需的。结论：eIF 4G在诺如病毒VPg依赖的翻译起始中起重要作用。意义：VPg-eIF 4G相互作用可能为特异性抑制诺如病毒翻译提供合适的靶点。病毒已经进化出多种机制来篡夺宿主细胞翻译机制，以使得在高水平细胞mRNA存在下能够翻译病毒基因组。诺如病毒是引起人类胃肠炎的主要原因之一，其作用机制依赖于翻译起始因子与病毒编码的VPg蛋白的相互作用，VPg蛋白共价连接在病毒RNA的5′端。为了进一步表征这种新的翻译起始机制，我们使用蛋白质组学来鉴定诺如病毒翻译起始因子复合物的组分。该方法揭示了VPg直接结合eIF 4F复合物，VPg和eIF 4G之间发生高亲和力相互作用。突变分析表明，VPg的C-末端区域对于VPg-eIF 4G相互作用是重要的;具有改变或破坏这种相互作用的突变的病毒是衰弱的或不能存活的。我们的研究结果揭示了蛋白质定向翻译起始的不寻常机制。
Background: Noroviruses use a virus-encoded protein, VPg, covalently linked to the viral RNA for translation. Results: The direct interaction of VPg with the central domain of eIF4G is required for norovirus translation. Conclusion: eIF4G plays a central role in norovirus VPg-dependent translation initiation. Significance: The VPg-eIF4G interaction may provide a suitable target for the specific inhibition of norovirus translation. Viruses have evolved a variety of mechanisms to usurp the host cell translation machinery to enable translation of the viral genome in the presence of high levels of cellular mRNAs. Noroviruses, a major cause of gastroenteritis in man, have evolved a mechanism that relies on the interaction of translation initiation factors with the virus-encoded VPg protein covalently linked to the 5′ end of the viral RNA. To further characterize this novel mechanism of translation initiation, we have used proteomics to identify the components of the norovirus translation initiation factor complex. This approach revealed that VPg binds directly to the eIF4F complex, with a high affinity interaction occurring between VPg and eIF4G. Mutational analyses indicated that the C-terminal region of VPg is important for the VPg-eIF4G interaction; viruses with mutations that alter or disrupt this interaction are debilitated or non-viable. Our results shed new light on the unusual mechanisms of protein-directed translation initiation.