SARS-CoV-2 main protease cleaves MAGED2 to antagonize host antiviral defense.
SARS-CoV-2 main protease cleaves MAGED2 to antagonize host antiviral defense.
复制标题
作者：
严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）是导致COVID-19全球大流行的病原体。SARS-CoV-2基因组编码一种主要蛋白酶（nsp5，也称为Mpro）和一种木瓜蛋白酶（nsp3，也称为PLpro），它们负责处理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可以切割人类MAGED2和其他哺乳动物的同源基因Gln-263。此外，SARS-CoV和MERS-CoV Mpro也能切割人类MAGED2，提示Mpro切割MAGED2是哺乳动物感染冠状病毒的一种进化保守机制。有趣的是，来自Beta变体的Mpro比野生型更有效地切割MAGED2，而来自Omicron的Mpro则相反。进一步研究表明，MAGED2在病毒复制阶段抑制SARS-CoV-2感染。从机制上讲，MAGED2通过其n端区域以rna依赖的方式与SARS-CoV-2核衣壳蛋白相关联，从而破坏SARS-CoV-2核衣壳蛋白与病毒基因组的相互作用，从而抑制病毒复制。当MAGED2被Mpro切割时，其n端会转运到细胞核中，截断的MAGED2无法抑制SARS-CoV-2的复制。这项工作不仅发现了MAGED2的抗病毒功能，而且为SARS-CoV-2 Mpro如何拮抗宿主抗病毒反应提供了新的见解。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。在这里，我们发现MAGED2可以被SARS-CoV-2主要蛋白酶（Mpro）在Gln-263位点切割。SARS-CoV和MERS-CoV Mpro也可以切割MAGED2，并且来自多个物种的MAGED2可以被SARS-CoV-2 Mpro切割。来自Beta变体的Mpro比野生型更有效地切割MAGED2，而Omicron则相反。MAGED2缺失可增强SARS-CoV-2感染，提示其对SARS-CoV-2感染具有抑制作用。从机制上讲，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端会转移到细胞核中。通过这种方式，Mpro解除了MAGED2对病毒复制的抑制。该研究提高了我们对复杂病毒-宿主相互作用的理解，并为治疗SARS-CoV-2感染提供了新的靶点。
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. 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.
登录
查看更多内容
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
5.4
作者：
Dagotto, Gabriel;Mercado, Noe B.;Barouch, Dan H.
通讯作者：
Barouch, Dan H.
影响因子：
6.4
作者：
Liu Y;Qin C;Rao Y;Ngo C;Feng JJ;Zhao J;Zhang S;Wang TY;Carriere J;Savas AC;Zarinfar M;Rice S;Yang H;Yuan W;Camarero JA;Yu J;Chen XS;Zhang C;Feng P
通讯作者：
Feng P
影响因子：
6.7
作者：
Ju X;Zhu Y;Wang Y;Li J;Zhang J;Gong M;Ren W;Li S;Zhong J;Zhang L;Zhang QC;Zhang R;Ding Q
通讯作者：
Ding Q