Pirh2 restricts influenza A virus replication by modulating short‐chain ubiquitination of its nucleoprotein
Pirh2 restricts influenza A virus replication by modulating short‐chain ubiquitination of its nucleoprotein
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DOI：
10.1096/fj.202200473r
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发表时间：
2022-09
期刊：
影响因子：
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通讯作者：
Huan Chen;Xiaoyu Gao;Shiying Zhao;Chenyi Bao;Xin Ming;Yingjuan Qian;Yan Zhou;Yong-Sam Jung
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文献类型：
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作者：
Huan Chen;Xiaoyu Gao;Shiying Zhao;Chenyi Bao;Xin Ming;Yingjuan Qian;Yan Zhou;Yong-Sam Jung
甲型流感病毒（IAV）依赖于病毒核糖核蛋白（vRNP）复合物来控制转录和复制。每个vRNP由与多个核蛋白（NP）和三聚体IAV RNA聚合酶复合物相关的一个病毒基因组RNA片段组成。先前的研究表明，宿主因子对vRNP组分（如NP）的翻译后修饰反过来会影响IAV的生命周期或调节宿主的抗病毒反应。在这项研究中，我们发现宿主E3泛素连接酶Pirh 2与NP相互作用并介导NP在赖氨酸351处的短链泛素化，这抑制了NP-PB 2相互作用和vRNP的形成。此外，我们发现敲低Pirh 2促进IAV复制，而过表达Pirh 2抑制IAV复制。然而，缺乏E3连接酶活性的Pirh 2-ΔRING未能抑制IAV感染。此外，我们发现Pirh 2对拯救的病毒WSN-K351 R的复制没有影响，WSN-K351 R在残基351处携带赖氨酸到精氨酸的取代。有趣的是，通过分析流感研究数据库中2011 - 2020年的人和禽IAV，我们发现26977人IAV中有99.18%编码赖氨酸，但9956禽IAV中有95.3%编码NP蛋白残基351的精氨酸。一致的是，Pirh 2的敲除未能促进两种禽流感样病毒H9 N2-W1和H9 N2-C1的繁殖，这两种病毒天然编码NP残基351处的精氨酸。总之，我们证明Pirh 2是通过调节NP的短链泛素化来限制IAV感染的宿主因子。同时，值得注意的是，Pirh 2靶向的NP的残基351可能与人类对禽流感样病毒的抗病毒应答的逃避有关。
Influenza A viruses (IAVs) rely on viral ribonucleoprotein (vRNP) complexes to control transcription and replication. Each vRNP consists of one viral genomic RNA segment associated with multiple nucleoproteins (NP) and a trimeric IAV RNA polymerase complex. Previous studies showed that post‐translational modifications of vRNP components, such as NP, by host factors would in turn affect the IAV life cycle or modulate host anti‐viral response. In this study, we found host E3 ubiquitin ligase Pirh2 interacted with NP and mediated short‐chain ubiquitination of NP at lysine 351, which suppressed NP‐PB2 interaction and vRNP formation. In addition, we showed that knockdown of Pirh2 promoted IAV replication, whereas overexpression of Pirh2 inhibited IAV replication. However, Pirh2‐ΔRING lacking E3 ligase activity failed to inhibit IAV infection. Moreover, we showed that Pirh2 had no effect on the replication of a rescued virus, WSN‐K351R, carrying lysine‐to‐arginine substitution at residue 351. Interestingly, by analyzing human and avian IAVs from 2011 to 2020 in influenza research databases, we found that 99.18% of 26 977 human IAVs encode lysine, but 95.3% of 9956 avian IAVs encode arginine at residue 351 of NP protein. Consistently, knockdown of Pirh2 failed to promote propagation of two avian‐like influenza viruses, H9N2‐W1 and H9N2‐C1, which naturally encode arginine at residue 351 of NP. Taken together, we demonstrated that Pirh2 is a host factor restricting IAV infection by modulating short‐chain ubiquitination of NP. Meanwhile, it is noteworthy that residue 351 of NP targeted by Pirh2 may associate with the evasion of human anti‐viral response against avian‐like influenza viruses.