P-bodies相关蛋白MOV10抑制病毒机制的研究

Influenza A virus is the main pathogen of influenza which could cause tremendous loss upon outbreak. IAV’s replication needs exploit host’s replication machinery, on the other hand, host evolves restrict factors which is part of host innate immunity to inhibit virus replication in cells. To screen these host proteins which is associated with IAV replication, we used NP as bait, and performed co-immunoprecipitation and followed by mass-spectrum analysis. We found P-bodies associated protein MOV10 is a NP interacting protein. As mRNA translation and degradation regulating apparatus, proteins in PB are involved in the restriction of many viruses. But PB’s role in IAV replication is lacking. Our previous study showed that MOV10 interacted with NP in a RNA dependent manner. MOV10 restricts IAV replication at early stage in both overexpressing and knocking down conditions. Moreover, our results showed MOV10 and NP colocalized at P-bodies in cell, suggesting MOV10 may restrict IAV replication in a PB dependent manner. Elucidating the mechanism of MOV10 restricting IAV may help us better understanding the role of PB in innate immunity against virus infection. On the other hand, our results showed that IAV infection caused reduction of MOV10 level, suggesting that IAV might encode an antagonist of MOV10. Studying the mechanism of IAV fights back MOV10 restriction could enrich our knowledge of how IAV antagonizing host innate immunity.

流感病毒A型是一种严重威胁人类健康病原体，它的复制需要利用宿主的复制机器；另一方面，细胞也进化出了能够天然抑制病毒复制的蛋白。我们利用质谱技术筛选这些与病毒复制相关的蛋白时，发现流感病毒的NP蛋白和P-bodies（PB）相关蛋白MOV10具有相互作用。PB作为细胞中mRNA翻译及代谢的重要细胞器，其中的蛋白参与了抑制多种病毒的复制，但对PB是否存在抑制流感病毒的机制并无确切报道。我们的前期结果发现MOV10能够抑制流感病毒的早期复制，并发现两者在细胞中共定位于PB中，提示MOV10有可能通过PB抑制流感病毒。对于MOV10抑制流感病毒机制的阐明有利于我们认识调节细胞mRNA代谢的细胞器PB在抗病毒的天然免疫过程中的作用。另一方面，我们发现病毒感染能够降低细胞中MOV10的表达，提示流感病毒可能存在拮抗MOV10的机制。对这一部分的研究能够丰富我们对流感病毒拮抗宿主天然免疫的认识。

A型流感病毒是一种严重威胁人类健康的病原体，它需要利用宿主进行自身的复制，而宿主也进化出能够抑制病毒复制的机制抵抗病毒感染。我们通过筛选与流感病毒NP蛋白相互作用的蛋白，发现细胞P-bodies蛋白MOV10与NP具有相互作用，并且在细胞中过表达MOV10能够抑制流感病毒的复制，而敲降MOV10促进流感病毒的复制，同时MOV10也能够抑制人群中的流行株A/H1N1pdm09和A/H3N2的感染。进一步研究发现，病毒进入细胞后，其vRNP能够与MOV10结合并定位于P-bodies中，导致病毒RNA的降解。MOV10抑制病毒的作用并不依赖于其解旋酶活性，而是依赖其与NP蛋白的相互作用，并且P-bodies的完整性也是必须的。此外，病毒编码的NS1蛋白能够拮抗MOV10的作用，首先，NS1结合MOV10并介导其通过溶酶体依赖的途径进行降解；其次，NS1降低NP和MOV10之间的相互作用。此研究大大丰富了我们对调节细胞mRNA代谢的P-bodies在抗病毒的天然免疫中的作用，同时提供了对流感病毒拮抗宿主天然免疫的认识。