SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species
Copyright policy )SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species
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.
- University of Queensland Australia
- University of Queensland Australia
- The University of Texas Medical Branch at Galveston United States
- The University of Texas System United States
- UNSW Sydney Australia
Chemical Sciences not elsewhere classified, Epidemiology, Coronaviruses, Immunology, Plant Biology, Coronavirus Papain-Like Proteases, Infectious and parasitic diseases, RC109-216, Biochemistry, Microbiology, Cell Line, Mice, Virology, Chiroptera, Drug Discovery, Animals, Humans, Amino Acid Sequence, TAB1, innate immunity, Coronavirus 3C Proteases, Cancer, NSP5 (3CLpro), Adaptor Proteins, Signal Transducing, NLRP12, SARS-CoV-2, NSP3 (PLpro), Intracellular Signaling Peptides and Proteins, Computational Biology, COVID-19, General Medicine, IRF3, QR1-502, Mental Health, Infectious Diseases, HEK293 Cells, Parasitology, protease activity, Interferon Regulatory Factor-3
Chemical Sciences not elsewhere classified, Epidemiology, Coronaviruses, Immunology, Plant Biology, Coronavirus Papain-Like Proteases, Infectious and parasitic diseases, RC109-216, Biochemistry, Microbiology, Cell Line, Mice, Virology, Chiroptera, Drug Discovery, Animals, Humans, Amino Acid Sequence, TAB1, innate immunity, Coronavirus 3C Proteases, Cancer, NSP5 (3CLpro), Adaptor Proteins, Signal Transducing, NLRP12, SARS-CoV-2, NSP3 (PLpro), Intracellular Signaling Peptides and Proteins, Computational Biology, COVID-19, General Medicine, IRF3, QR1-502, Mental Health, Infectious Diseases, HEK293 Cells, Parasitology, protease activity, Interferon Regulatory Factor-3
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