小柯机器人

近日，德国歌德大学Ivan Dikic及其小组的最新研究表明，木瓜蛋白酶样蛋白酶调节SARS-CoV-2病毒传播和先天免疫。这一研究成果于2020年7月29日在线发表在国际学术期刊《自然》上。

研究人员提供了SARS-CoV-2 PLpro（SCoV2-PLpro）的生化、结构和功能表征，并概述了SARS-CoV PLpro（SCoV-PLpro）在控制宿主干扰素（IFN）和NF-κB途径方面的差异。尽管SCoV2-PLpro和SCoV-PLpro具有83％的序列同一性，但它们显示出不同的宿主底物偏好。特别是，SCoV2-PLpro优先切割泛素样蛋白ISG15，而SCoV-PLpro主要靶向泛素链。SCoV2-PLpro与ISG15形成复合物的晶体结构揭示了与ISG15氨基末端泛素样结构域的独特相互作用，从而突出了这种高亲和力和特异性。

此外，感染后，SCoV2-PLpro有助于从干扰素反应因子3（IRF3）切割ISG15，并减弱I型干扰素反应。重要的是，用GRL-0617抑制SCoV2-PLpro会削弱病毒诱导的细胞致病作用，促进抗病毒干扰素途径并减少感染细胞中的病毒复制。这些结果突出了一种双重治疗策略，即靶向SCoV2-PLpro可以抑制SARS-CoV-2感染并促进抗病毒免疫。

据悉，木瓜蛋白酶样蛋白酶PLpro是加工病毒多蛋白来产生功能性复制酶复合物并使病毒能够传播所需的必需冠状病毒酶。PLpro还涉及切割宿主蛋白上的蛋白质翻译后修饰，从而作为针对宿主抗病毒免疫反应的逃避机制。

附：英文原文

Title: Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity

Author: Donghyuk Shin, Rukmini Mukherjee, Diana Grewe, Denisa Bojkova, Kheewoong Baek, Anshu Bhattacharya, Laura Schulz, Marek Widera, Ahmad Reza Mehdipour, Georg Tascher, Paul P. Geurink, Alexander Wilhelm, Gerbrand J. van der Heden van Noort, Huib Ovaa, Stefan Mller, Klaus-Peter Knobeloch, Krishnaraj Rajalingam, Brenda A. Schulman, Jindrich Cinatl, Gerhard Hummer, Sandra Ciesek, Ivan Dikic

Issue&Volume: 2020-07-29

Abstract: The papain-like protease PLpro is an essential coronavirus enzyme required for processing viral polyproteins to generate a functional replicase complex and enable viral spread1,2. PLpro is also implicated in cleaving proteinaceous post-translational modifications on host proteins as an evasion mechanism against host anti-viral immune responses3–5. Here, we provide biochemical, structural and functional characterization of the SARS-CoV-2 PLpro (SCoV2-PLpro) and outline differences to SARS-CoV PLpro (SCoV-PLpro) in controlling host interferon (IFN) and NF-κB pathways. While SCoV2-PLpro and SCoV-PLpro share 83% sequence identity, they exhibit different host substrate preferences. In particular, SCoV2-PLpro preferentially cleaves the ubiquitin-like 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 this high affinity and specificity. Furthermore, upon infection, SCoV2-PLpro contributes to the cleavage of ISG15 from interferon responsive factor 3 (IRF3) and attenuates type I interferon responses. Importantly, inhibition of SCoV2-PLpro with GRL-0617 impairs the virus-induced cytopathogenic effect, fosters the anti-viral interferon pathway and reduces viral replication in infected cells. These results highlight a dual therapeutic strategy in which targeting of SCoV2-PLpro can suppress SARS-CoV-2 infection and promote anti-viral immunity.

DOI: 10.1038/s41586-020-2601-5

Source: https://www.nature.com/articles/s41586-020-2601-5

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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