An NS-segment exonic splicing enhancer regulates influenza A virus replication in mammalian cells.
An NS-segment exonic splicing enhancer regulates influenza A virus replication in mammalian cells.
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DOI：
10.1038/ncomms14751
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发表时间：
2017-03-21
影响因子：
16.6
通讯作者：
Chen H
中科院分区：
文献类型：
--
作者：
Huang X;Zheng M;Wang P;Mok BW;Liu S;Lau SY;Chen P;Liu YC;Liu H;Chen Y;Song W;Yuen KY;Chen H
流感病毒利用宿主剪接机制处理从M和NS片段表达的病毒mRNAs。通过基因分析和功能鉴定，我们发现H7N9病毒的NS片段包含一个独特的G540A替换，位于甲型流感病毒NEP基因中一个未知的外显子剪接增强子(ESE)基序中。G540A支持在哺乳动物细胞中复制病毒，同时保留在禽类细胞中的复制能力。宿主剪接调节因子SF2与该ESE相互作用，调节NEP/NS1 mRNA的剪接，G540A替换影响SF2-ESE的相互作用。NS1蛋白直接与核内的SF2相互作用，并在病毒复制过程中调节NS mRNAs的剪接。我们证明了NEP/NS1 mRNA的剪接是通过一个顺式NEP-ESE基序来调节的，并提示一个独特的NEP-ESE可能有助于为H7N9病毒提供在禽类宿主中有效循环和在哺乳动物细胞中复制的能力。一些正在传播的甲型禽流感病毒可以感染人类，但使物种跳跃的机制尚不清楚。这里，Huang et al.确定H7N9禽流感病毒NEP中影响NS片段剪接效率并支持病毒在禽类和哺乳动物细胞中复制的核苷酸。
Influenza virus utilizes host splicing machinery to process viral mRNAs expressed from both M and NS segments. Through genetic analysis and functional characterization, we here show that the NS segment of H7N9 virus contains a unique G540A substitution, located within a previously undefined exonic splicing enhancer (ESE) motif present in the NEP mRNA of influenza A viruses. G540A supports virus replication in mammalian cells while retaining replication ability in avian cells. Host splicing regulator, SF2, interacts with this ESE to regulate splicing of NEP/NS1 mRNA and G540A substitution affects SF2–ESE interaction. The NS1 protein directly interacts with SF2 in the nucleus and modulates splicing of NS mRNAs during virus replication. We demonstrate that splicing of NEP/NS1 mRNA is regulated through a cis NEP-ESE motif and suggest a unique NEP-ESE may contribute to provide H7N9 virus with the ability to both circulate efficiently in avian hosts and replicate in mammalian cells. Some circulating avian influenza A viruses can infect humans, but the mechanism enabling species jump is poorly understood. Here, Huang et al. identify a nucleotide in NEP of avian H7N9 viruses that affects splicing efficiency of the NS segment and supports virus replication in avian and mammalian cells.