The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
SARS-CoV-2 proteases PLpro and 3CLpro cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species
Open accessAbstract
Abstract The genome of SARS-CoV-2 (SARS2) encodes for two viral proteases (NSP3/ papain-like protease and NSP5/ 3C-like protease or major protease) that are responsible for cleaving viral polyproteins for successful replication. NSP3 and NSP5 of SARS-CoV (SARS1) are known interferon antagonists. Here, we examined whether the protease function of SARS2 NSP3 and NSP5 target proteins involved in the host innate immune response. We designed a fluorescent based cleavage assay to rapidly screen the protease activity of NSP3 and NSP5 on a library of 71 human innate immune proteins (HIIPs), covering most pathways involved in human innate immunity. By expressing each of these HIIPs with a genetically encoded fluorophore in a cell-free system and titrating in the recombinant protease domain of NSP3 or NSP5, we could readily detect cleavage of cognate HIIPs on SDS-page gels. 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 IL-6 and inflammatory response observed in COVID-19 patients. Surprisingly, both NLRP12 and TAB1 have each two distinct cleavage sites. We demonstrate that in mice, the second cleavage site of NLRP12 is absent. 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 in-depth studies into the pathophysiology of COVID-19 and should facilitate the search or development of more effective animal models for severe COVID-19. Finally, we discovered that one particular species of bats, David’s Myotis, possesses the five cleavage sites found in humans for NLRP12, TAB1 and IRF3. These bats are endemic from the Hubei province in China and we discuss its potential role as reservoir for the evolution of SARS1 and SASR2.
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Cites
Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus
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“geted for post-translational modifications upon infection [45,46], leading to its homodimerization (PDB: 1QWT, Figure 2(F)), translocation into the nucleus”
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Cited by
The Multiple Roles of Interferon Regulatory Factor family in Health and Disease
Wang, L., Zhu, Y., Zhang, N., Xian, Y., Tang, Y., Ye, J., Reza, F., He, G., Wen, X., & Jiang, X. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01980-4 · Cited by 178
Recognition and cleavage of human tRNA methyltransferase TRMT1 by the SARS-CoV-2 main protease
D'Oliviera, A., Dai, X., Mottaghinia, S., Olson, S., Geissler, E. P., Etienne, L., Zhang, Y., & Mugridge, J. S. (2025) · eLife · doi:10.7554/elife.91168.3 · Cited by 13
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Inhibition of SARS-CoV-2 3CL protease by the anti-viral chimeric protein RetroMAD1
Chan, L.-C., Mat Yassim, A. S., Ahmad Fuaad, A. A. H., Leow, T. C., Sabri, S., Radin Yahaya, R. S., & Abu Bakar, A. M. S. (2023) · Scientific Reports · doi:10.1038/s41598-023-47511-z · Cited by 5
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Recognition and cleavage of human tRNA methyltransferase TRMT1 by the SARS-CoV-2 main protease
D'Oliviera, A., Dai, X., Mottaghinia, S., Olson, S., Geissler, E. P., Etienne, L., Zhang, Y., & Mugridge, J. S. (2025) · eLife · doi:10.7554/elife.91168 · Cited by 2
Metadata
- Authors
- Moustaqil, M., Ollivier, E., Chiu, H.-P., Van Tol, S., Rudolffi-Soto, P., Stevens, C., Bhumkar, A., Hunter, D. J. B., Freiberg, A. N., Jacques, D., Lee, B., Sierecki, E., & Gambin, Y.
- Venue
- Emerging Microbes & Infections
- Publisher
- Informa UK Limited
- Published
- 2021-01
- Volume
- 10
- Issue
- 1
- Pages
- 178-195
- ISSN
- 2222-1751 (ISSN-L)
- OpenAlex
- W3115414062
- Cited by
- 283
- References
- 9
- FWCI
- 5.19
- Type
- journal article
- Language
- en
- Open access
- gold
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