1. Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells.
- Author
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Planès R, Pinilla M, Santoni K, Hessel A, Passemar C, Lay K, Paillette P, Valadão AC, Robinson KS, Bastard P, Lam N, Fadrique R, Rossi I, Pericat D, Bagayoko S, Leon-Icaza SA, Rombouts Y, Perouzel E, Tiraby M, Zhang Q, Cicuta P, Jouanguy E, Neyrolles O, Bryant CE, Floto AR, Goujon C, Lei FZ, Martin-Blondel G, Silva S, Casanova JL, Cougoule C, Reversade B, Marcoux J, Ravet E, and Meunier E
- Subjects
- Caspase 3 metabolism, Humans, Lung metabolism, Lung virology, Peptide Hydrolases genetics, Peptide Hydrolases metabolism, Phosphate-Binding Proteins genetics, Phosphate-Binding Proteins metabolism, Pore Forming Cytotoxic Proteins genetics, Pore Forming Cytotoxic Proteins metabolism, Pyroptosis, COVID-19 genetics, COVID-19 metabolism, COVID-19 virology, Coronavirus 3C Proteases genetics, Coronavirus 3C Proteases metabolism, Epithelial Cells metabolism, Inflammasomes genetics, Inflammasomes metabolism, NLR Proteins genetics, NLR Proteins metabolism, SARS-CoV-2 enzymology, SARS-CoV-2 genetics, SARS-CoV-2 metabolism, SARS-CoV-2 pathogenicity
- Abstract
Inflammation observed in SARS-CoV-2-infected patients suggests that inflammasomes, proinflammatory intracellular complexes, regulate various steps of infection. Lung epithelial cells express inflammasome-forming sensors and constitute the primary entry door of SARS-CoV-2. Here, we describe that the NLRP1 inflammasome detects SARS-CoV-2 infection in human lung epithelial cells. Specifically, human NLRP1 is cleaved at the Q333 site by multiple coronavirus 3CL proteases, which triggers inflammasome assembly and cell death and limits the production of infectious viral particles. Analysis of NLRP1-associated pathways unveils that 3CL proteases also inactivate the pyroptosis executioner Gasdermin D (GSDMD). Subsequently, caspase-3 and GSDME promote alternative cell pyroptosis. Finally, analysis of pyroptosis markers in plasma from COVID-19 patients with characterized severe pneumonia due to autoantibodies against, or inborn errors of, type I interferons (IFNs) highlights GSDME/caspase-3 as potential markers of disease severity. Overall, our findings identify NLRP1 as a sensor of SARS-CoV-2 infection in lung epithelia., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
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