严重急性呼吸道综合征冠状病毒2(SARS-CoV-2)是导致COVID-19全球大流行的病原体。SARS-CoV-2基因组编码主要蛋白酶(nsp5,也称为Mpro)和木瓜蛋白酶样蛋白酶(nsp3,也称为PLpro),它们负责加工病毒多蛋白以组装功能性复制酶复合物。在这项研究中,我们发现SARS-CoV-2的Mpro可以在Gln-263处切割人MAGED2和其他哺乳动物直向同源物。此外,SARS-CoV和MERS-CoVMpro也可以切割人MAGED2,这表明Mpro切割MAGED2是哺乳动物中冠状病毒感染的进化保守机制。有趣的是,来自Beta变体的Mpro比野生型更有效地切割MAGED2,但是OmicronMpro是相反的。进一步的研究表明MAGED2在病毒复制步骤抑制SARS-CoV-2感染。机械上,MAGED2通过其N末端区域以RNA依赖的方式与SARS-CoV-2核衣壳蛋白相关,这破坏了SARS-CoV-2核衣壳蛋白与病毒基因组之间的相互作用,从而抑制病毒复制。当MAGED2被Mpro切割时,MAGED2的N端将转移到细胞核中,截短的MAGED2不能抑制SARS-CoV-2的复制。这项工作不仅发现了MAGED2的抗病毒功能,而且还提供了有关SARS-CoV-2Mpro如何拮抗宿主抗病毒反应的新见解。重要性限制严重急性呼吸综合征冠状病毒2(SARS-CoV-2)感染的宿主因素仍然难以捉摸。这里,我们发现MAGED2可以被SARS-CoV-2主要蛋白酶(Mpro)在Gln-263裂解。SARS-CoV和MERS-CoVMpro也可以切割MAGED2,并且SARS-CoV-2Mpro可以切割来自多个物种的MAGED2。来自Beta变体的Mpro比野生型更有效地切割MAGED2,但Omicron正好相反.MAGED2消耗增强SARS-CoV-2感染,提示其在SARS-CoV-2感染中的抑制作用。机械上,MAGED2通过破坏核衣壳和病毒基因组之间的相互作用来限制SARS-CoV-2的复制。当MAGED2被切割时,它的N端将转移到细胞核中。这样,Mpro缓解MAGED2对病毒复制的抑制。这项研究提高了我们对复杂的病毒-宿主相互作用的理解,并提供了治疗SARS-CoV-2感染的新靶标。
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent causing the global pandemic of COVID-19. SARS-CoV-2 genome encodes a main protease (nsp5, also called Mpro) and a papain-like protease (nsp3, also called PLpro), which are responsible for processing viral polyproteins to assemble a functional replicase complex. In this study, we found that Mpro of SARS-CoV-2 can cleave human MAGED2 and other mammalian orthologs at Gln-263. Moreover, SARS-CoV and MERS-CoV Mpro can also cleave human
MAGED2, suggesting
MAGED2 cleavage by Mpro is an evolutionarily conserved mechanism of coronavirus infection in mammals. Intriguingly, Mpro from Beta variant cleaves MAGED2 more efficiently than wild type, but Omicron Mpro is opposite. Further studies show that MAGED2 inhibits SARS-CoV-2 infection at viral replication step. Mechanistically, MAGED2 is associated with SARS-CoV-2 nucleocapsid protein through its N-terminal region in an RNA-dependent manner, and this disrupts the interaction between SARS-CoV-2 nucleocapsid protein and viral genome, thus inhibiting viral replication. When
MAGED2 is cleaved by Mpro, the N-terminal of
MAGED2 will translocate into the nucleus, and the truncated
MAGED2 is unable to suppress SARS-CoV-2 replication. This work not only discovers the antiviral function of MAGED2 but also provides new insights into how SARS-CoV-2 Mpro antagonizes host antiviral response. IMPORTANCE Host factors that restrict severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remain elusive. Here, we found that MAGED2 can be cleaved by SARS-CoV-2 main protease (Mpro) at Gln-263. SARS-CoV and MERS-CoV Mpro can also cleave
MAGED2, and
MAGED2 from multiple species can be cleaved by SARS-CoV-2 Mpro. Mpro from Beta variant cleaves MAGED2 more efficiently efficiently than wild type, but Omicron is the opposite. MAGED2 depletion enhances SARS-CoV-2 infection, suggesting its inhibitory role in SARS-CoV-2 infection. Mechanistically, MAGED2 restricts SARS-CoV-2 replication by disrupting the interaction between nucleocapsid and viral genomes. When MAGED2 is cleaved, its N-terminal will translocate into the nucleus. In this way, Mpro relieves
MAGED2\' inhibition on viral replication. This study improves our understanding of complex viral-host interaction and provides novel targets to treat SARS-CoV-2 infection.