Influenza virus targets the mRNA export machinery and the nuclear pore complex
Influenza virus targets the mRNA export machinery and the nuclear pore complex
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DOI：
10.1073/pnas.0610977104
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发表时间：
2007-02-06
影响因子：
11.1
通讯作者：
Fontoura, Beatriz M. A.
中科院分区：
文献类型：
--
作者：
Satterly, Neal;Tsai, Pei-Ling;Fontoura, Beatriz M. A.
甲型流感病毒的NS 1蛋白是致病所必需的主要毒力因子。NS 1通过抑制宿主信号转导和基因表达来损害先天性和获得性免疫，但其作用机制仍有待充分阐明。我们发现NS 1与NXF 1/TAP、p15/NXT、Rael/mrnp 41和E1 B-AP 5形成抑制复合物，这些复合物是mRNA输出机制的关键成分，它们与mRNA和核孔蛋白相互作用，引导mRNA通过核孔复合物。NXF 1、p15或Rae 1水平升高可逆转NS 1诱导的mRNA输出阻断。此外，流感病毒下调Nup 98，一种核孔蛋白，是mRNA输出因子的对接位点。这些mRNA输出因子的表达降低使得细胞高度容许流感病毒复制，表明mRNA输出机制的关键成分的适当水平保护免受流感病毒复制。由于Nup 98和Rae 1是由干扰素诱导的，因此该途径的下调可能是促进病毒复制的病毒策略。这些发现证实了以前未描述的流感介导的病毒-宿主相互作用，并为可能干扰流感感染的潜在分子疗法提供了见解。
The NS1 protein of influenza A virus is a major virulence factor that is essential for pathogenesis. NS1 functions to impair innate and adaptive immunity by inhibiting host signal transduction and gene expression, but its mechanisms of action remain to be fully elucidated. We show here that NS1 forms an inhibitory complex with NXF1/TAP, p15/NXT, Rael/mrnp41, and E1B-AP5, which are key constituents of the mRNA export machinery that interact with both mRNAs and nucleoporins to direct mRNAs through the nuclear pore complex. Increased levels of NXF1, p15, or Rae1 revert the mRNA export blockage induced by NS1. Furthermore, influenza virus down-regulates Nup98, a nucleoporin that is a docking site for mRNA export factors. Reduced expression of these mRNA export factors renders cells highly permissive to influenza virus replication, demonstrating that proper levels of key constituents of the mRNA export machinery protect against influenza virus replication. Because Nup98 and Rae1 are induced by interferons, downregulation of this pathway is likely a viral strategy to promote viral replication. These findings demonstrate previously undescribed influenza-mediated viral-host interactions and provide insights into potential molecular therapies that may interfere with influenza infection.