SARS-CoV-2 Nsp5 Demonstrates Two Distinct Mechanisms Targeting RIG-I and MAVS To Evade the Innate Immune Response.
SARS-CoV-2 Nsp5 Demonstrates Two Distinct Mechanisms Targeting RIG-I and MAVS To Evade the Innate Immune Response.
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DOI：
10.1128/mbio.02335-21
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发表时间：
2021-10-26
期刊：
影响因子：
6.4
通讯作者：
Feng P
中科院分区：
文献类型：
--
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
新出现的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起了全球大流行，死亡率和发病率惊人。SARS-CoV-2的高复制和传播与以前密切相关的冠状病毒明显不同，其潜在的分子机制仍不清楚。先天免疫防御是限制病毒复制的物理屏障。我们在这里报告的SARS-CoV-2 Nsp 5主要蛋白酶的目标RIG-I和线粒体抗病毒信号（MAVS）蛋白通过两种不同的抑制机制。具体而言，Nsp 5从RIG-I切割10个最N端氨基酸并剥夺其激活MAVS的能力，而Nsp 5促进MAVS的泛素化和蛋白酶体介导的降解。因此，Nsp 5以酶依赖性方式有效抑制双链RNA（dsRNA）对干扰素（IFN）的诱导。一种合成的小分子抑制剂减弱了Nsp 5介导的细胞RIG-1和MAVS的破坏以及SARS-CoV-2非结构蛋白的加工，从而恢复了先天免疫应答并阻止了SARS-CoV-2的复制。这项工作为SARS-CoV-2的免疫逃避策略提供了新的见解，并为治疗2019年冠状病毒病（COVID-19）患者提供了潜在的抗病毒剂。
Newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic with astonishing mortality and morbidity. The high replication and transmission of SARS-CoV-2 are remarkably distinct from those of previous closely related coronaviruses, and the underlying molecular mechanisms remain unclear. The innate immune defense is a physical barrier that restricts viral replication. We report here that the SARS-CoV-2 Nsp5 main protease targets RIG-I and mitochondrial antiviral signaling (MAVS) protein via two distinct mechanisms for inhibition. Specifically, Nsp5 cleaves off the 10 most-N-terminal amino acids from RIG-I and deprives it of the ability to activate MAVS, whereas Nsp5 promotes the ubiquitination and proteosome-mediated degradation of MAVS. As such, Nsp5 potently inhibits interferon (IFN) induction by double-stranded RNA (dsRNA) in an enzyme-dependent manner. A synthetic small-molecule inhibitor blunts the Nsp5-mediated destruction of cellular RIG-I and MAVS and processing of SARS-CoV-2 nonstructural proteins, thus restoring the innate immune response and impeding SARS-CoV-2 replication. This work offers new insight into the immune evasion strategy of SARS-CoV-2 and provides a potential antiviral agent to treat CoV disease 2019 (COVID-19) patients.
影响因子：
6.7
作者：
Feng H;Dong X;Negaard A;Feng P
通讯作者：
Feng P