Zheng Zhou-Qin, Wang Su-Yun, Xu Zhi-Sheng, Fu Yu-Zhi, Wang Yan-Yi
Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China.
University of Chinese Academy of Sciences, Beijing, China.
Cell Discov. 2021 May 25;7(1):38. doi: 10.1038/s41421-021-00275-0.
The newly emerging coronavirus SARS-CoV-2 causes severe lung disease and substantial mortality. How the virus evades host defense for efficient replication is not fully understood. In this report, we found that the SARS-CoV-2 nucleocapsid protein (NP) impaired stress granule (SG) formation induced by viral RNA. SARS-CoV-2 NP associated with the protein kinase PKR after dsRNA stimulation. SARS-CoV-2 NP did not affect dsRNA-induced PKR oligomerization, but impaired dsRNA-induced PKR phosphorylation (a hallmark of its activation) as well as SG formation. SARS-CoV-2 NP also targeted the SG-nucleating protein G3BP1 and impaired G3BP1-mediated SG formation. Deficiency of PKR or G3BP1 impaired dsRNA-triggered SG formation and increased SARS-CoV-2 replication. The NP of SARS-CoV also targeted both PKR and G3BP1 to impair dsRNA-induced SG formation, whereas the NP of MERS-CoV targeted PKR, but not G3BP1 for the impairment. Our findings suggest that SARS-CoV-2 NP promotes viral replication by impairing formation of antiviral SGs, and reveal a conserved mechanism on evasion of host antiviral responses by highly pathogenic human betacoronaviruses.
新出现的冠状病毒SARS-CoV-2会导致严重的肺部疾病并造成大量死亡。该病毒如何逃避宿主防御以实现高效复制尚不完全清楚。在本报告中，我们发现SARS-CoV-2核衣壳蛋白（NP）会损害病毒RNA诱导的应激颗粒（SG）形成。在双链RNA（dsRNA）刺激后，SARS-CoV-2 NP与蛋白激酶PKR结合。SARS-CoV-2 NP不影响dsRNA诱导的PKR寡聚化，但会损害dsRNA诱导的PKR磷酸化（其激活的标志）以及SG形成。SARS-CoV-2 NP还靶向SG成核蛋白G3BP1并损害G3BP1介导的SG形成。PKR或G3BP1的缺陷会损害dsRNA触发的SG形成并增加SARS-CoV-2复制。SARS-CoV的NP也靶向PKR和G3BP1以损害dsRNA诱导的SG形成，而MERS-CoV的NP靶向PKR，但不靶向G3BP1以造成损害。我们的研究结果表明，SARS-CoV-2 NP通过损害抗病毒SG的形成来促进病毒复制，并揭示了高致病性人类β冠状病毒逃避宿主抗病毒反应的保守机制。
