ABSTRACT 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 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.
【저자키워드】 SARS-CoV-2, Innate immunity, IRF3, TAB1, Protease activity, NSP3 (PLpro), NSP5 (3CLpro), NLRP12, 【초록키워드】 COVID-19, innate immune response, SARS-COV-2 infection, Genome, cytokine, protease, molecular mechanism, Replication, Protein, pathophysiology, cleavage, nsp5, disease, function, COVID-19 patients, Inflammatory response, IFN response, motif, homolog, ENCODE, polyprotein, Host, Direct, responsible, lack, example, involved, contribute, explain, cleaved, cleave, cleaving, in-vitro assay, mediated cleavage, 【제목키워드】 3CLpro, PLPro, disease, Critical, SARS-CoV-2 protease, implication, cleave, inflammatory pathway,