Inhibition of translation and immune responses by the virulence factor Nsp1 of SARS-CoV-2.
Inhibition of translation and immune responses by the virulence factor Nsp1 of SARS-CoV-2.
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DOI：
10.1038/s41392-020-00350-0
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发表时间：
2020-10-09
影响因子：
39.3
通讯作者：
Kutateladze TG
中科院分区：
文献类型：
--
作者：
Vann KR;Tencer AH;Kutateladze TG
SARS-CoV-2毒力因子的结构分析对于疫苗和抗病毒疗法的开发至关重要。最近的冷冻电镜结构的病毒蛋白Nsp 1结合到人类核糖体机器揭示了翻译关闭和阻断宿主免疫反应的机制。1 COVID-19全球大流行已肆虐全球数月，并继续对公众健康构成巨大威胁。此次疫情是过去20年来最严重的一次大流行，截至2020年8月，发病率达到1800万。COVID-19的病原体-严重急性呼吸道综合征冠状病毒-2（SARS-CoV-2）-属于高致病性β-冠状病毒组，还包括SARS-CoV和MERS-CoV，它们在2002年和2012年引起呼吸道疾病。SARS-CoV-2和SARS-CoV病毒密切相关，在它们的单链RNA基因组中共享约80%的核苷酸同一性。SARS-CoV-2基因组编码四种结构蛋白，如刺突蛋白（S）、包膜蛋白（E）、膜蛋白（M）和核衣壳蛋白（N）、几种非结构蛋白（Nsp）和开放阅读框（ORF 1a和ORF 1ab）前体多聚蛋白，这些蛋白在宿主细胞中被蛋白水解裂解，产生一组额外的Nsp，包括Nsp 1（图1a）。SARS冠状病毒Nsp 1是其主要毒力因子。它与小核糖体亚基结合，通过阻断信使RNA（mRNA）翻译并促进宿主mRNA降解来抑制宿主蛋白质的产生。重要的是，通过诱导宿主蛋白（包括干扰素）的翻译几乎完全关闭，Nsp 1破坏了先天免疫系统的防御机制，并促进了病毒复制。由于其在免疫反应失调中的重要作用，SARS-CoV-2的Nsp 1可能是抗COVID-19的一个有吸引力的药理学靶点。最近Thomas等1和Schubert等2对SARS-CoV-2的Nsp 1的结构研究阐明了Nsp 1与人核糖体机制结合的分子机制，并可用于指导抑制剂和疫苗的开发。Thoms等人1报道，Nsp 1与纯化的人核糖体40 S亚基和80 S核糖体强烈相关，但不与主动翻译的多聚核糖体相关，并且Nsp 1的存在阻止了体外和HEK 293 T细胞中的mRNA翻译。作者还发现，Nsp 1的C-末端残基K164和H165，包括在SARS-CoV中保守的KH基序，是这种相互作用和抑制翻译所必需的。KH基序的突变降低了Nsp 1与核糖体亚基结合并阻断宿主mRNA翻译的能力。
Structural analysis of SARS-CoV-2 virulence factors is crucial for the development of vaccines and anti-viral therapeutics. Recent cryo-EM structures of the viral protein Nsp1 bound to the human ribosomal machinery shed light onto the mechanism of translational shutdown and blockage of host immune response. 1 The global pandemic of COVID-19 has been ravaging the world for several months and continues posing an enormous threat to public health. This outbreak is the most serious pandemic occurred in the last 2 decades with morbidity reaching 18 million as of August 2020. The causative agent of COVID-19—Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2)—belongs to the group of highly pathogenic beta-coronaviruses that also includes SARS-CoV and MERS-CoV, which caused respiratory diseases in 2002 and 2012. The SARS-CoV-2 and SARS-CoV viruses are closely related and share~ 80% nucleotide identity in their single-stranded RNA genomes. The SARS-CoV-2 genome encodes four structural proteins, such as Spike (S), Envelope (E), Membrane (M) and Nucleocapsid (N), several non-structural proteins (Nsp), and the open-reading frame (ORF1a and ORF1ab) precursor polyproteins that are proteolytically cleaved in the host cells producing an additional set of Nsps, including Nsp1 (Fig. 1 a). Nsp1 of SARS-CoV has been shown to act as a major virulence factor. It binds to the small ribosomal subunit, inhibiting production of host proteins by blocking messenger RNA (mRNA) translation and promoting degradation of host mRNA. Importantly, by inducing a near complete shutdown of translation of host proteins, including interferons, Nsp1 destroys the defense mechanisms of the innate immune system and facilitates viral replication. Owning to its crucial role in immune response dysregulation, Nsp1 of SARS-CoV-2 may represent an attractive pharmacological target in the fight against COVID-19.Recent structural studies of Nsp1 of SARS-CoV-2 by Thoms et al. 1 and Schubert et al. 2 illuminated the molecular mechanism by which Nsp1 binds to the human ribosomal machinery and can be instrumental in guiding the development of inhibitors and vaccines. Thoms et al. 1 report that Nsp1 strongly associates with purified human ribosomal 40S subunit and 80S ribosomes, but not with actively translating polyribosomes and that the presence of Nsp1 precludes mRNA translation in vitro and in HEK293T cells. The authors also found that the C-terminal residues K164 and H165 of Nsp1, comprising the KH motif, which is conserved in SARS-CoV, are required for this interaction and inhibition of translation. Mutation of the KH motif reduces the ability of Nsp1 to associate with ribosomal subunits and block host mRNA translation.
影响因子：
64.8
作者：
Gordon, David E.;Jang, Gwendolyn M.;Krogan, Nevan J.
通讯作者：
Krogan, Nevan J.
影响因子：
56.9
作者：
Thoms, Matthias;Buschauer, Robert;Beckmann, Roland
通讯作者：
Beckmann, Roland
影响因子：
56.9
作者：
Gao, Yan;Yan, Liming;Rao, Zihe
通讯作者：
Rao, Zihe