SARS-CoV-2 nucleocapsid protein phase separates with G3BPs to disassemble stress granules and facilitate viral production

新冠病毒N蛋白与G3BP发生相分离从而促进应激颗粒解组装和病毒产生

A key to tackling the coronavirus disease 2019(COVID-19)pandemic is to understand how severe acute respiratory syndrome coronavirus 2(SARS-Co V-2)manages to outsmart host antiviral defense mechanisms.Stress granules(SGs),which are assembled during viral infection and function to sequester host and viral m RNAs and proteins,are part of the antiviral responses.Here,we show that the SARS-Co V-2 nucleocapsid(N)protein,an RNA binding protein essential for viral production,interacted with RasGTPase-activating protein SH3-domain-binding protein(G3 BP)and disrupted SG assembly,both of which require intrinsically disordered region1(IDR1)in N protein.The N protein partitioned into SGs through liquid-liquid phase separation with G3 BP,and blocked the interaction of G3 BP1 with other SG-related proteins.Moreover,the N protein domains important for phase separation with G3 BP and SG disassembly were required for SARS-Co V-2 viral production.We propose that N protein-mediated SG disassembly is crucial for SARS-Co V-2 production.

新型冠状病毒SARS-CoV-2的爆发导致全世界数以百万计人员的感染和死亡,有效的治疗和干预措施对疫情的控制至关重要.然而到目前为止,新冠病毒逃过宿主抗病毒反应的机制尚未明确.病毒感染宿主细胞时,宿主能够迅速启动细胞的压力应答机制,终止细胞内的蛋白翻译,形成应激颗粒.本研究发现新型冠状病毒核衣壳蛋白(N蛋白)—一种在病毒组装过程非常关键的RNA结合蛋白,与宿主的G3BP蛋白(应激颗粒组装过程中关键的RNA结合蛋白)相互作用,并促进应激颗粒的解组装.N蛋白通过与G3BP发生相分离从而渗入应激颗粒中,阻断了G3BP与其他应激颗粒内蛋白的相互作用,最终破坏了应激颗粒的组装.这一N蛋白介导的相分离过程最终会促进病毒逃过宿主的抗病毒反应,从而有利于病毒的产生.