Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity
Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity
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DOI：
10.1038/s41586-020-2601-5
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发表时间：
2020-07-29
期刊：
影响因子：
64.8
通讯作者：
Dikic, Ivan
中科院分区：
文献类型：
--
作者：
Shin, Donghyuk;Mukherjee, Rukmini;Dikic, Ivan
生物化学，严重急性呼吸综合征冠状病毒2的结构和功能研究（SARS-CoV-2）木瓜蛋白酶样蛋白酶PLpro揭示它通过优先切割泛素样干扰素刺激基因15蛋白（ISG 15）来调节宿主抗病毒反应，并将这种蛋白酶鉴定为冠状病毒疾病的潜在治疗靶点2019木瓜蛋白酶样蛋白酶PLpro是一种必需的冠状病毒酶，其是加工病毒多聚蛋白以产生功能性复制酶复合物并使病毒传播所需的（1，2）。PLpro还涉及切割宿主蛋白上的蛋白质性翻译后修饰，作为针对宿主抗病毒免疫应答的逃避机制（3-5）。在这里，我们进行严重急性呼吸综合征冠状病毒2（SARS-CoV-2）PLpro（SCoV 2-PLpro）的生化，结构和功能特性，并概述与SARS-CoV PLpro（SCoV-PLpro）在调节宿主干扰素和NF-κ B途径的差异。SCoV 2-PLpro和SCoV-PLpro共享83%的序列同一性，但表现出不同的宿主底物偏好; SCoV 2-PLpro优先切割泛素样干扰素刺激的基因15蛋白（ISG 15），而SCoV-PLpro主要靶向泛素链。与ISG 15复合的SCoV 2-PLpro的晶体结构揭示了与ISG 15的氨基末端泛素样结构域的独特相互作用，突出了这些相互作用的高亲和力和特异性。此外，在感染时，SCoV 2-PLpro有助于从干扰素应答因子3（IRF 3）切割ISG 15并减弱I型干扰素应答。值得注意的是，用GRL-0617抑制SCoV 2-PLpro削弱了病毒诱导的致细胞病变作用，维持了抗病毒干扰素途径并减少了感染细胞中的病毒复制。这些结果突出了一种潜在的双重治疗策略，其中靶向SCoV 2-PLpro可以抑制SARS-CoV-2感染并促进抗病毒免疫。
Biochemical, structural and functional studies on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) papain-like protease PLpro reveal that it regulates host antiviral responses by preferentially cleaving the ubiquitin-like interferon-stimulated gene 15 protein (ISG15) and identify this protease as a potential therapeutic target for coronavirus disease 2019 (COVID-19).The papain-like protease PLpro is an essential coronavirus enzyme that is required for processing viral polyproteins to generate a functional replicase complex and enable viral spread(1,2). PLpro is also implicated in cleaving proteinaceous post-translational modifications on host proteins as an evasion mechanism against host antiviral immune responses(3-5). Here we perform biochemical, structural and functional characterization of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PLpro (SCoV2-PLpro) and outline differences with SARS-CoV PLpro (SCoV-PLpro) in regulation of host interferon and NF-kappa B pathways. SCoV2-PLpro and SCoV-PLpro share 83% sequence identity but exhibit different host substrate preferences; SCoV2-PLpro preferentially cleaves the ubiquitin-like interferon-stimulated gene 15 protein (ISG15), whereas SCoV-PLpro predominantly targets ubiquitin chains. The crystal structure of SCoV2-PLpro in complex with ISG15 reveals distinctive interactions with the amino-terminal ubiquitin-like domain of ISG15, highlighting the high affinity and specificity of these interactions. Furthermore, upon infection, SCoV2-PLpro contributes to the cleavage of ISG15 from interferon responsive factor 3 (IRF3) and attenuates type I interferon responses. Notably, inhibition of SCoV2-PLpro with GRL-0617 impairs the virus-induced cytopathogenic effect, maintains the antiviral interferon pathway and reduces viral replication in infected cells. These results highlight a potential dual therapeutic strategy in which targeting of SCoV2-PLpro can suppress SARS-CoV-2 infection and promote antiviral immunity.