Eukaryotic Translation Elongation Factor 1 Delta Inhibits the Nuclear Import of the Nucleoprotein and PA-PB1 Heterodimer of Influenza A Virus
Eukaryotic Translation Elongation Factor 1 Delta Inhibits the Nuclear Import of the Nucleoprotein and PA-PB1 Heterodimer of Influenza A Virus
复制标题
真核翻译延伸因子 1 Delta 抑制甲型流感病毒核蛋白和 PA-PB1 异二聚体的核输入
DOI：
10.1128/jvi.01391-20
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发表时间：
2021-01-01
影响因子：
5.4
通讯作者：
Zhou, Hongbo
中科院分区：
文献类型：
--
作者：
Gao, Qingxia;Yang, Cha;Zhou, Hongbo
甲型流感病毒是导致人类和动物感染的一种呼吸道疾病——流感的主要原因。与大多数其他RNA病毒不同，IAV的转录和复制发生在细胞核内。因此，vRNPs必须被导入细胞核进行病毒转录和复制，这需要宿主蛋白的参与。然而，涉及核进口的iav -宿主相互作用的机制仍然知之甚少。在这里，我们发现eEF1D是流感病毒生命周期的一种新型抑制剂。重要的是，eEF1D破坏了NP与输入α5的相互作用以及PB1与RanBP5的相互作用，从而阻碍了vRNP的核输入。我们的研究不仅揭示了IAV vRNP核输入的分子机制，而且为抗病毒药物的开发提供了潜在的抗流感靶点。甲型流感病毒（IAV）的病毒核糖核蛋白（vRNP）在细胞核内负责病毒RNA转录和复制，其功能依赖于宿主因子。先前的研究表明，真核翻译延伸因子1 δ (eEF1D)可能与RNP亚基有关，但其在IAV复制中的作用尚不清楚。在这里，我们发现eEF1D是IAV复制的抑制剂，因为敲除eEF1D导致病毒产量显著增加。eEF1D与RNP亚基聚合酶酸性蛋白（PA）、聚合酶碱性1 （PB1）、聚合酶碱性2 （PB2）以及核蛋白（NP）以rna依赖的方式相互作用。进一步研究发现，eEF1D阻断了IAV的NP和PA-PB1异源二聚体的核输入，从而抑制vRNP的组装、病毒聚合酶活性和病毒RNA的合成。总之，我们的研究表明eEF1D通过抑制RNP亚基的核输入来负向调节IAV复制，这不仅揭示了eEF1D在IAV复制中的新作用，而且为vRNP蛋白的核输入机制提供了新的见解。甲型流感病毒是流感的主要病因，流感是人类和动物的一种呼吸道疾病。与大多数其他RNA病毒不同，IAV的转录和复制发生在细胞核内。因此，vRNPs必须被导入细胞核进行病毒转录和复制，这需要宿主蛋白的参与。然而，涉及核进口的iav -宿主相互作用的机制仍然知之甚少。在这里，我们发现eEF1D是流感病毒生命周期的一种新型抑制剂。重要的是，eEF1D破坏了NP与输入α5的相互作用以及PB1与RanBP5的相互作用，从而阻碍了vRNP的核输入。我们的研究不仅揭示了IAV vRNP核输入的分子机制，而且为抗病毒药物的开发提供了潜在的抗流感靶点。
Influenza A virus is the major cause of influenza, a respiratory disease in humans and animals. Different from most other RNA viruses, the transcription and replication of IAV occur in the cell nucleus. Therefore, the vRNPs must be imported into the nucleus for viral transcription and replication, which requires participation of host proteins. However, the mechanisms of the IAV-host interactions involved in nuclear import remain poorly understood. Here, we identified eEF1D as a novel inhibitor for the influenza virus life cycle. Importantly, eEF1D impaired the interaction between NP and importin α5 and the interaction between PB1 and RanBP5, which impeded the nuclear import of vRNP. Our studies not only reveal the molecular mechanisms of the nuclear import of IAV vRNP but also provide potential anti-influenza targets for antiviral development. ABSTRACT The viral ribonucleoprotein (vRNP) of the influenza A virus (IAV) is responsible for the viral RNA transcription and replication in the nucleus, and its functions rely on host factors. Previous studies have indicated that eukaryotic translation elongation factor 1 delta (eEF1D) may associate with RNP subunits, but its roles in IAV replication are unclear. Herein, we showed that eEF1D was an inhibitor of IAV replication because knockout of eEF1D resulted in a significant increase in virus yield. eEF1D interacted with RNP subunits polymerase acidic protein (PA), polymerase basic 1 (PB1), polymerase basic 2 (PB2), and also with nucleoprotein (NP) in an RNA-dependent manner. Further studies revealed that eEF1D impeded the nuclear import of NP and PA-PB1 heterodimer of IAV, thereby suppressing the vRNP assembly, viral polymerase activity, and viral RNA synthesis. Together, our studies demonstrate eEF1D negatively regulating the IAV replication by inhibition of the nuclear import of RNP subunits, which not only uncovers a novel role of eEF1D in IAV replication but also provides new insights into the mechanisms of nuclear import of vRNP proteins. IMPORTANCE Influenza A virus is the major cause of influenza, a respiratory disease in humans and animals. Different from most other RNA viruses, the transcription and replication of IAV occur in the cell nucleus. Therefore, the vRNPs must be imported into the nucleus for viral transcription and replication, which requires participation of host proteins. However, the mechanisms of the IAV-host interactions involved in nuclear import remain poorly understood. Here, we identified eEF1D as a novel inhibitor for the influenza virus life cycle. Importantly, eEF1D impaired the interaction between NP and importin α5 and the interaction between PB1 and RanBP5, which impeded the nuclear import of vRNP. Our studies not only reveal the molecular mechanisms of the nuclear import of IAV vRNP but also provide potential anti-influenza targets for antiviral development.