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.