EMBL Australia Node for Single Molecule Sciences, and School of Medical Sciences, Botany Road, The University of New South Wales, Sydney, Australia.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Emerg Microbes Infect. 2021 Dec;10(1):178-195. doi: 10.1080/22221751.2020.1870414.
The genome of SARS-CoV-2 encodes two viral proteases (NSP3/papain-like protease and NSP5/3C-like protease) that are responsible for cleaving viral polyproteins during replication. Here, we discovered new functions of the NSP3 and NSP5 proteases of SARS-CoV-2, demonstrating that they could directly cleave proteins involved in the host innate immune response. We identified 3 proteins that were specifically and selectively cleaved by NSP3 or NSP5: IRF-3, and NLRP12 and TAB1, respectively. Direct cleavage of IRF3 by NSP3 could explain the blunted Type-I IFN response seen during SARS-CoV-2 infections while NSP5 mediated cleavage of NLRP12 and TAB1 point to a molecular mechanism for enhanced production of cytokines and inflammatory responThe genome of SARS-CoV-2 encodes two viral proteases (NSP3/papain-like protease and NSP5/3C-like protease) that are responsible for cleaving viral polyproteins during replication. Here, we discovered new functions of the NSP3 and NSP5 proteases of SARS-CoV-2, demonstrating that they could directly cleave proteins involved in the host innate immune response. We identified 3 proteins that were specifically and selectively cleaved by NSP3 or NSP5: IRF-3, and NLRP12 and TAB1, respectively. Direct cleavage of IRF3 by NSP3 could explain the blunted Type-I IFN response seen during SARS-CoV-2 infections while NSP5 mediated cleavage of NLRP12 and TAB1 point to a molecular mechanism for enhanced production of cytokines and inflammatory response observed in COVID-19 patients. We demonstrate that in the mouse NLRP12 protein, one of the recognition site is not cleaved in our assay. We pushed this comparative alignment of IRF-3 and NLRP12 homologs and show that the lack or presence of cognate cleavage motifs in IRF-3 and NLRP12 could contribute to the presentation of disease in cats and tigers, for example. Our findings provide an explanatory framework for indepth studies into the pathophysiology of COVID-19.
SARS-CoV-2 的基因组编码两种病毒蛋白酶（NSP3/木瓜蛋白酶样蛋白酶和 NSP5/3C 样蛋白酶），它们负责在复制过程中切割病毒多蛋白。在这里，我们发现了 SARS-CoV-2 的 NSP3 和 NSP5 蛋白酶的新功能，证明它们可以直接切割参与宿主先天免疫反应的蛋白质。我们鉴定了 3 种被 NSP3 或 NSP5 特异性和选择性切割的蛋白质：IRF-3 以及 NLRP12 和 TAB1。NSP3 对 IRF3 的直接切割可以解释 SARS-CoV-2 感染期间观察到的 I 型 IFN 反应迟钝，而 NSP5 介导的 NLRP12 和 TAB1 的切割表明了增强细胞因子和炎症反应的分子机制。在 COVID-19 患者中观察到。我们证明在小鼠 NLRP12 蛋白中，我们的测定中没有切割一个识别位点。我们推动了 IRF-3 和 NLRP12 同源物的这种比较性比对，并表明 IRF-3 和 NLRP12 中同源切割基序的缺失或存在可能导致猫和老虎出现疾病。我们的发现为深入研究 COVID-19 的病理生理学提供了一个解释框架。
