Journal
EMERGING MICROBES & INFECTIONS
Volume 10, Issue 1, Pages 178-195Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/22221751.2020.1870414
Keywords
SARS-CoV-2; innate immunity; protease activity; NSP3 (PLpro); NSP5 (3CLpro); IRF3; NLRP12; TAB1
Categories
Funding
- NIH [AI123449, AI125536]
- Department of Microbiology at ISMMS
- MoST Postdoctoral Research Abroad Program (Ministry of Science and Technology, Taiwan) [110-2917-I-564020]
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The study revealed that the proteases NSP3 and NSP5 of SARS-CoV-2 can cleave proteins involved in host immune responses, shedding light on the mechanisms behind enhanced inflammatory responses in COVID-19 patients. The direct cleavage of specific proteins by these proteases provides insights into the pathophysiology of the disease.
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 in-vitro 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.
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