TRIM41-Mediated Ubiquitination of Nucleoprotein Limits Influenza A Virus Infection
TRIM41-Mediated Ubiquitination of Nucleoprotein Limits Influenza A Virus Infection
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DOI：
10.1128/jvi.00905-18
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发表时间：
2018-08-01
影响因子：
5.4
通讯作者：
Li, Shitao
中科院分区：
文献类型：
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作者：
Patil, Girish;Zhao, Mengmeng;Li, Shitao
甲型流感病毒（IAV）是一种高度传播的呼吸道病原体，也是世界范围内发病和死亡的主要原因。核蛋白（Nucleoprotein，NP）是一种丰富的IAV蛋白，在病毒生命周期的多个阶段中发挥重要作用。我们最近对IAV-宿主相互作用网络的蛋白质组学研究发现，泛素E3连接酶TRIM 41（含三重基序41）与NP相互作用。然而，TRIM 41在IAV感染中的作用尚不清楚。在这里，我们报告TRIM 41通过其SPRY结构域与NP相互作用。此外，TRIM 41在肺上皮细胞中组成型表达，并且TRIM 41的过表达抑制IAV感染。相反，RNA干扰（RNAi）和TRIM 41的敲除增加宿主对IAV感染的易感性。作为泛素E3连接酶，TRIM 41在体外和细胞中泛素化NP。缺乏E3连接酶活性的TRIM 41突变体不能抑制IAV感染，表明E3连接酶活性对于TRIM 41抗病毒功能是不可缺少的。机制分析进一步揭示了多聚泛素化导致NP蛋白降解和病毒抑制。综合这些观察结果，TRIM 41是一种组成型表达的内在IAV限制因子，靶向NP进行遍在化和蛋白质降解。重要信息流感控制策略依赖于每年的免疫接种，需要频繁更新疫苗，这并不总是万无一失的过程。此外，目前的抗病毒药物也正在失去效力，因为新的病毒株通常对常规治疗无效。因此，迫切需要找到新的抗病毒机制并基于这些机制开发治疗药物。靶向病毒-宿主界面是一种新兴的新策略，因为控制病毒复制活性的宿主因子将是理想的候选者，并且细胞蛋白在药物介导的选择性压力下不太可能突变。在这里，我们表明，泛素E3连接酶TRIM 41是一个内在的主机限制因子IAV。TRIM 41直接结合病毒核蛋白并靶向其进行泛素化和蛋白酶体降解，从而限制病毒感染。利用这种天然防御途径可能为开发针对流感病毒的抗病毒药物开辟新途径。
Influenza A virus (IAV) is a highly transmissible respiratory pathogen and a major cause of morbidity and mortality around the world. Nucleoprotein (NP) is an abundant IAV protein essential for multiple steps of the viral life cycle. Our recent proteomic study of the IAV-host interaction network found that TRIM41 (tripartite motif-containing 41), a ubiquitin E3 ligase, interacted with NP. However, the role of TRIM41 in IAV infection is unknown. Here, we report that TRIM41 interacts with NP through its SPRY domain. Furthermore, TRIM41 is constitutively expressed in lung epithelial cells, and overexpression of TRIM41 inhibits IAV infection. Conversely, RNA interference (RNAi) and knockout of TRIM41 increase host susceptibility to IAV infection. As a ubiquitin E3 ligase, TRIM41 ubiquitinates NP in vitro and in cells. The TRIM41 mutant lacking E3 ligase activity fails to inhibit IAV infection, suggesting that the E3 ligase activity is indispensable for TRIM41 antiviral function. Mechanistic analysis further revealed that the polyubiquitination leads to NP protein degradation and viral inhibition. Taking these observations together, TRIM41 is a constitutively expressed intrinsic IAV restriction factor that targets NP for ubiquitination and protein degradation.IMPORTANCE Influenza control strategies rely on annual immunization and require frequent updates of the vaccine, which is not always a foolproof process. Furthermore, the current antivirals are also losing effectiveness as new viral strains are often refractory to conventional treatments. Thus, there is an urgent need to find new antiviral mechanisms and develop therapeutic drugs based on these mechanisms. Targeting the virus-host interface is an emerging new strategy because host factors controlling viral replication activity will be ideal candidates, and cellular proteins are less likely to mutate under drug-mediated selective pressure. Here, we show that the ubiquitin E3 ligase TRIM41 is an intrinsic host restriction factor to IAV. TRIM41 directly binds the viral nucleoprotein and targets it for ubiquitination and proteasomal degradation, thereby limiting viral infection. Exploitation of this natural defense pathway may open new avenues to develop antiviral drugs targeting the influenza virus.