DnaJA1/Hsp40 Is Co-Opted by Influenza A Virus To Enhance Its Viral RNA Polymerase Activity
DnaJA1/Hsp40 Is Co-Opted by Influenza A Virus To Enhance Its Viral RNA Polymerase Activity
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甲型流感病毒利用 DnaJA1/Hsp40 来增强其病毒 RNA 聚合酶活性
DOI：
10.1128/jvi.02475-14
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发表时间：
2014-12-01
影响因子：
5.4
通讯作者：
Deng, Tao
中科院分区：
文献类型：
--
作者：
Cao, Mengmeng;Wei, Candong;Deng, Tao
甲型流感病毒的RNA依赖RNA聚合酶(RdRp)是由PB1、PB2和PA亚基组成的异源三聚体复合体。宿主因子和RdRp的三个亚基之间的相互作用是使病毒RNA合成发生在感染细胞的细胞核中的关键。在这项研究中，我们新发现了宿主因子Dna JA1，它是I型Dna J/Hsp40家族的成员，对流感病毒的复制起着积极的调节作用。我们发现Dna JA1与bPB2和PA亚基结合，在体内和体外都能增强病毒RNA的合成。此外，流感病毒感染后，Dna JA1可从胞浆转位到胞核。Dna JA1的易位特异性地伴随着PB1-PA核进口。有趣的是，我们观察到Dna JA1对病毒RNA合成的影响主要依赖于其C末端底物结合结构域，而不是其典型的J结构域，而J结构域通常介导调节Hsp70 ATPase活性所需的Hsp70-Dna J相互作用。因此，我们认为Dna JA1被甲型流感病毒所选择进入细胞核，并以Hsp70辅伴侣不依赖的方式增强其RNA聚合酶的活性。在这项研究中，我们新发现了一种宿主蛋白Dna JA1/Hsp40，它被甲型流感病毒RNA聚合酶所增选，以增强其在感染细胞的细胞核中的RNA合成。我们发现，在流感病毒复制过程中，Dna JA1与PB2和PA亚基结合，并随着PB1-PA二聚体的核输入而移位到细胞核中。有趣的是，Dna JA1的作用主要依赖于它的C-末端底物结合结构域，而不是它典型的J结构域，后者是其Hsp70辅伴侣功能所必需的。据我们所知，这是第一个关于Hsp40成员的报告，该成员专门参与调节流感病毒RNA聚合酶。靶向聚合酶亚单位和Dna JA1之间的相互作用可能为开发抗病毒药物提供一种新的策略。
The RNA-dependent RNA polymerase (RdRp) of influenza A virus is a heterotrimeric complex composed of the PB1, PB2, and PA subunits. The interplay between host factors and the three subunits of the RdRp is critical to enable viral RNA synthesis to occur in the nuclei of infected cells. In this study, we newly identified host factor DnaJA1, a member of the type I DnaJ/Hsp40 family, acting as a positive regulator for influenza virus replication. We found that DnaJA1 associates with the bPB2 and PA subunits and enhances viral RNA synthesis both in vivo and in vitro. Moreover, DnaJA1 could be translocated from cytoplasm into the nucleus upon influenza virus infection. The translocation of DnaJA1 is specifically accompanied by PB1-PA nuclear import. Interestingly, we observed that the effect of DnaJA1 on viral RNA synthesis is mainly dependent on its C-terminal substrate-binding domain and not on its typical J domain, while the J domain normally mediates the Hsp70-DnaJ interaction required for regulating Hsp70 ATPase activity. Therefore, we propose that DnaJA1 is co-opted by the influenza A virus to enter the nucleus and to enhance its RNA polymerase activity in an Hsp70 cochaperone-independent manner.IMPORTANCEThe interplay between host factors and influenza virus RNA polymerase plays a critical role in determining virus pathogenicity and host adaptation. In this study, we newly identified a host protein, DnaJA1/Hsp40, that is co-opted by influenza A virus RNA polymerase to enhance its viral RNA synthesis in the nuclei of infected cells. We found that DnaJA1 associates with both PB2 and PA subunits and translocates into the nucleus along with the nuclear import of the PB1-PA dimer during influenza virus replication. Interestingly, the effect of DnaJA1 is mainly dependent on its C-terminal substrate-binding domain and not on its typical J domain, which is required for its Hsp70 cochaperone function. To our knowledge, this is the first report on a member of the Hsp40s that is specifically involved in regulating influenza virus RNA polymerase. Targeting the interactions between polymerase subunits and DnaJA1 may provide a novel strategy to develop antiviral drugs.