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 c...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2021-01-01
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| Series: | Emerging Microbes and Infections |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/22221751.2020.1870414 |
| _version_ | 1818987879527874560 |
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| author | Mehdi Moustaqil Emma Ollivier Hsin-Ping Chiu Sarah Van Tol Paulina Rudolffi-Soto Christian Stevens Akshay Bhumkar Dominic J. B. Hunter Alexander N. Freiberg David Jacques Benhur Lee Emma Sierecki Yann Gambin |
| author_facet | Mehdi Moustaqil Emma Ollivier Hsin-Ping Chiu Sarah Van Tol Paulina Rudolffi-Soto Christian Stevens Akshay Bhumkar Dominic J. B. Hunter Alexander N. Freiberg David Jacques Benhur Lee Emma Sierecki Yann Gambin |
| author_sort | Mehdi Moustaqil |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T19:13:42Z |
| format | Article |
| id | doaj.art-abb04dd2b53e469d9a1bf3b2624c8bc7 |
| institution | Directory Open Access Journal |
| issn | 2222-1751 |
| language | English |
| last_indexed | 2024-12-20T19:13:42Z |
| publishDate | 2021-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Emerging Microbes and Infections |
| spelling | doaj.art-abb04dd2b53e469d9a1bf3b2624c8bc72022-12-21T19:29:10ZengTaylor & Francis GroupEmerging Microbes and Infections2222-17512021-01-0110117819510.1080/22221751.2020.1870414SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across speciesMehdi Moustaqil0Emma Ollivier1Hsin-Ping Chiu2Sarah Van Tol3Paulina Rudolffi-Soto4Christian Stevens5Akshay Bhumkar6Dominic J. B. Hunter7Alexander N. Freiberg8David Jacques9Benhur Lee10Emma Sierecki11Yann Gambin12EMBL Australia Node for Single Molecule Sciences, and School of Medical Sciences, Botany Road, The University of New South Wales, Sydney, AustraliaEMBL Australia Node for Single Molecule Sciences, and School of Medical Sciences, Botany Road, The University of New South Wales, Sydney, AustraliaDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USADepartment of Microbiology and Immunology, Institute for Human Infections and Immunity, The University of Texas Medical Branch, Galveston, TX, USAEMBL Australia Node for Single Molecule Sciences, and School of Medical Sciences, Botany Road, The University of New South Wales, Sydney, AustraliaDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USAEMBL Australia Node for Single Molecule Sciences, and School of Medical Sciences, Botany Road, The University of New South Wales, Sydney, AustraliaEMBL Australia Node for Single Molecule Sciences, and School of Medical Sciences, Botany Road, The University of New South Wales, Sydney, AustraliaDepartment of Pathology, Institute for Human Infections and Immunity, The University of Texas Medical Branch, Galveston, TX, USAEMBL Australia Node for Single Molecule Sciences, and School of Medical Sciences, Botany Road, The University of New South Wales, Sydney, AustraliaDepartment of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USAEMBL Australia Node for Single Molecule Sciences, and School of Medical Sciences, Botany Road, The University of New South Wales, Sydney, AustraliaEMBL Australia Node for Single Molecule Sciences, and School of Medical Sciences, Botany Road, The University of New South Wales, Sydney, AustraliaThe 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.https://www.tandfonline.com/doi/10.1080/22221751.2020.1870414SARS-CoV-2innate immunityprotease activityNSP3 (PLpro)NSP5 (3CLpro)IRF3 |
| spellingShingle | Mehdi Moustaqil Emma Ollivier Hsin-Ping Chiu Sarah Van Tol Paulina Rudolffi-Soto Christian Stevens Akshay Bhumkar Dominic J. B. Hunter Alexander N. Freiberg David Jacques Benhur Lee Emma Sierecki Yann Gambin SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species Emerging Microbes and Infections SARS-CoV-2 innate immunity protease activity NSP3 (PLpro) NSP5 (3CLpro) IRF3 |
| title | SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species |
| title_full | SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species |
| title_fullStr | SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species |
| title_full_unstemmed | SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species |
| title_short | SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species |
| title_sort | sars cov 2 proteases plpro and 3clpro cleave irf3 and critical modulators of inflammatory pathways nlrp12 and tab1 implications for disease presentation across species |
| topic | SARS-CoV-2 innate immunity protease activity NSP3 (PLpro) NSP5 (3CLpro) IRF3 |
| url | https://www.tandfonline.com/doi/10.1080/22221751.2020.1870414 |
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