Host adaptive mutations in the 2009 H1N1 pandemic influenza A virus PA gene regulate translation efficiency of viral mRNAs via GRSF1.
Host adaptive mutations in the 2009 H1N1 pandemic influenza A virus PA gene regulate translation efficiency of viral mRNAs via GRSF1.
复制标题
DOI：
10.1038/s42003-022-04082-5
复制
发表时间：
2022-10-17
影响因子：
5.9
通讯作者：
Takimoto, Toru
中科院分区：
文献类型：
--
作者：
Lutz, Michael;Schmierer, Jordana;Takimoto, Toru
禽类是甲型流感病毒传染给人类的主要天然宿主。甲型禽流感病毒基因，包括三种病毒聚合酶基因 PA、PB1 和 PB2，需要宿主适应性突变才能允许病毒在人类中复制和传播。此前，来自 2009 pH1N1 病毒聚合酶的 PA 被发现含有宿主适应性突变，导致病毒聚合酶活性增强。通过量化翻译和 mRNA 转录，我们发现 2009 pH1N1 PA 和相关的宿主适应性突变导致更高的翻译效率。这是由于病毒 mRNA 的胞质积累增强，而这依赖于宿主 RNA 结合蛋白 GRSF1。病毒 mRNA 中 GRSF1 结合位点的突变以及 GRSF1 敲低会降低病毒 mRNA 的胞质积累和翻译效率。这项研究确定了一种以前未被认识的机制，PA 中的宿主适应性突变通过该机制调节病毒复制和宿主适应。重要的是，这些结果提供了对 IAV 宿主适应过程的更深入了解，并揭示了 GRSF1 在 IAV 生命周期中的重要性。禽类和人类甲型流感病毒聚合酶之间的比较表明，2009 pH1N1 中 PA 亚基的突变增强了病毒 mRNA 的胞质积累和翻译，其方式依赖于 RNA 结合蛋白 GRSF1。
Avian species are the major natural reservoir from which pandemic influenza A viruses can be introduced to humans. Avian influenza A virus genes, including the three viral polymerase genes, PA, PB1 and PB2, require host-adaptive mutations to allow for viral replication and transmission in humans. Previously, PA from the 2009 pH1N1 viral polymerase was found to harbor host-adaptive mutations leading to enhanced viral polymerase activity. By quantifying translation and mRNA transcription, we found that the 2009 pH1N1 PA, and the associated host-adaptive mutations, led to greater translation efficiency. This was due to enhanced cytosolic accumulation of viral mRNA, which was dependent on the host RNA binding protein GRSF1. Mutations to the GRSF1 binding site in viral mRNA, as well as GRSF1 knockdown, reduced cytosolic accumulation and translation efficiency of viral mRNAs. This study identifies a previously unrecognized mechanism by which host-adaptive mutations in PA regulate viral replication and host adaptation. Importantly, these results provide greater insight into the host adaptation process of IAVs and reveal the importance of GRSF1 in the lifecycle of IAV. A comparison between avian and human influenza A virus polymerases suggests that mutations in the PA subunit from 2009 pH1N1 enhanced cytosolic accumulation and translation of viral mRNA, in a manner dependent on the RNA binding protein, GRSF1.
登录
查看更多内容
DOI：
10.1016/j.bbagen.2020.129678
发表时间：
2020-11-01
影响因子：
3
作者：
Dumoulin, Bernhard;Ufer, Christoph;Sofi, Sajad
通讯作者：
Sofi, Sajad
影响因子：
5.4
作者：
Hayashi, Tsuyoshi;Chaimayo, Chutikarn;Takimoto, Toru
通讯作者：
Takimoto, Toru
影响因子：
6.7
作者：
Chaimayo C;Dunagan M;Hayashi T;Santoso N;Takimoto T
通讯作者：
Takimoto T
影响因子：
5.6
作者：
de Rozières CM;Pequeno A;Shahabi S;Lucas TM;Godula K;Ghosh G;Joseph S
通讯作者：
Joseph S
影响因子：
5.4
作者：
Bussey, Kendra A.;Bousse, Tatiana L.;Takimoto, Toru
通讯作者：
Takimoto, Toru