Sumoylation of Influenza A Virus Nucleoprotein Is Essential for Intracellular Trafficking and Virus Growth
Sumoylation of Influenza A Virus Nucleoprotein Is Essential for Intracellular Trafficking and Virus Growth
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甲型流感病毒核蛋白的苏酰化对于细胞内运输和病毒生长至关重要
DOI：
10.1128/jvi.00509-14
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发表时间：
2014-08-01
影响因子：
5.4
通讯作者：
Xu, Ke
中科院分区：
文献类型：
--
作者：
Han, Qinglin;Chang, Chong;Xu, Ke
摘要 病毒利用宿主翻译后修饰来获取自身利益。最近有报道称，甲型流感病毒蛋白与宿主苏酰化系统广泛相互作用。因此，包括 NS1 和 M1 在内的多种病毒蛋白被苏酰化以促进病毒复制。然而，甲型流感病毒对苏酰化的利用程度尚不完全清楚。在这项研究中，我们发现甲型流感病毒核蛋白（NP）是 NP 转染细胞和病毒感染细胞中 SUMO 化的真正靶标。我们进一步发现NP在最N末端的两个残基，赖氨酸4和7处被苏酰化，并且NP的赖氨酸7处的苏酰化在不同甲型流感病毒亚型和毒株中高度保守，包括最近出现的人类H7N9病毒。虽然 NP 稳定性和聚合酶活性几乎不受 sumoylation 的影响，但 NP sumoylation 缺陷的 WSN-NPK4,7R 病毒表现出 NP 的早期细胞质定位。与野生型WSN病毒相比，WSN-NPK4,7R病毒的生长高度减弱，并且7位赖氨酸残基对于病毒的生存是不可或缺的，正如回复病毒的迅速出现所表明的那样。因此，甲型流感病毒 NP 的苏酰化对于 NP 的细胞内运输和病毒生长至关重要，这说明苏酰化是甲型流感病毒广泛利用的在其宿主中生存的关键策略。重要性 宿主翻译后修饰是病毒为了自身利益而重点攻击的目标。我们和其他人之前报道过甲型流感病毒与宿主苏酰化系统广泛相互作用。然而，病毒苏酰化的功能结果尚未完全了解。在这里，我们发现甲型流感病毒核蛋白（NP）是病毒复制的重要组成部分，是SUMO的新靶点。这是第一项发现来自不同甲型流感病毒（包括最近出现的H7N9）的NP在保守的赖氨酸7处发生苏酰化的研究。我们的数据进一步说明甲型流感病毒NP的苏酰化对于NP的细胞内运输和病毒生长至关重要，表明甲型流感病毒深度依赖苏酰化在宿主细胞中生存。因此，下调病毒苏酰化的策略可能是一种潜在的抗病毒治疗。
ABSTRACT Viruses take advantage of host posttranslational modifications for their own benefit. It was recently reported that influenza A virus proteins interact extensively with the host sumoylation system. Thereby, several viral proteins, including NS1 and M1, are sumoylated to facilitate viral replication. However, to what extent sumoylation is exploited by influenza A virus is not fully understood. In this study, we found that influenza A virus nucleoprotein (NP) is a bona fide target of sumoylation in both NP-transfected cells and virus-infected cells. We further found that NP is sumoylated at the two most N-terminal residues, lysines 4 and 7, and that sumoylation at lysine 7 of NP is highly conserved across different influenza A virus subtypes and strains, including the recently emerged human H7N9 virus. While NP stability and polymerase activity are little affected by sumoylation, the NP sumoylation-defective WSN-NPK4,7R virus exhibited early cytoplasmic localization of NP. The growth of the WSN-NPK4,7R virus was highly attenuated compared to that of the wild-type WSN virus, and the lysine residue at position 7 is indispensable for the virus's survival, as illustrated by the rapid emergence of revertant viruses. Thus, sumoylation of influenza A virus NP is essential for intracellular trafficking of NP and for virus growth, illustrating sumoylation as a crucial strategy extensively exploited by influenza A virus for survival in its host. IMPORTANCE Host posttranslational modifications are heavily targeted by viruses for their own benefit. We and others previously reported that influenza A virus interacts extensively with the host sumoylation system. However, the functional outcomes of viral sumoylation are not fully understood. Here we found that influenza A virus nucleoprotein (NP), an essential component for virus replication, is a new target of SUMO. This is the first study to find that NP from different influenza A viruses, including recently emerged H7N9, is sumoylated at conserved lysine 7. Our data further illustrated that sumoylation of influenza A virus NP is essential for intracellular trafficking of NP and virus growth, indicating that influenza A virus relies deeply on sumoylation to survive in host cells. Strategies to downregulate viral sumoylation could thus be a potential antiviral treatment.