The dynamic proteome of influenza A virus infection identifies M segment splicing as a host range determinant
The dynamic proteome of influenza A virus infection identifies M segment splicing as a host range determinant
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DOI：
10.1038/s41467-019-13520-8
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发表时间：
2019-12-04
影响因子：
16.6
通讯作者：
Selbach, Matthias
中科院分区：
文献类型：
--
作者：
Bogdanow, Boris;Wang, Xi;Selbach, Matthias
当来自动物宿主的毒株获得在人类中感染和传播的能力时，就会发生大流行性甲型流感病毒（IAV）爆发。这种物种屏障的分子基础还不完全清楚。在这里，我们结合联合收割机代谢脉冲标记和定量蛋白质组学监测蛋白质合成后感染的人类细胞与人类和鸟类适应IAV株，并观察病毒蛋白质合成的显着差异。最重要的是，基质蛋白M1是由鸟类适应菌株低效产生的。我们表明，从鸟类适应菌株的M1生产受损是由增加剪接的M段RNA的替代亚型。菌株特异性M片段剪接由3'剪接位点控制，并且在功能上对于允许感染是重要的。计算机模拟和生物化学证据表明，禽类适应的M片段进化出了与人类适应的序列不同的保守RNA结构特征。因此，我们确定M段RNA剪接作为病毒宿主范围决定因素。
Pandemic influenza A virus (IAV) outbreaks occur when strains from animal reservoirs acquire the ability to infect and spread among humans. The molecular basis of this species barrier is incompletely understood. Here we combine metabolic pulse labeling and quantitative proteomics to monitor protein synthesis upon infection of human cells with a human-and a bird-adapted IAV strain and observe striking differences in viral protein synthesis. Most importantly, the matrix protein M1 is inefficiently produced by the bird-adapted strain. We show that impaired production of M1 from bird-adapted strains is caused by increased splicing of the M segment RNA to alternative isoforms. Strain-specific M segment splicing is controlled by the 3' splice site and functionally important for permissive infection. In silico and biochemical evidence shows that avian-adapted M segments have evolved different conserved RNA structure features than human-adapted sequences. Thus, we identify M segment RNA splicing as a viral host range determinant.