Dataset Information

Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells.

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.

SUBMITTER: Planes R

PROVIDER: S-EPMC9108100 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells.

Planès Rémi R Pinilla Miriam M Santoni Karin K Hessel Audrey A Passemar Charlotte C Lay Kenneth K Paillette Perrine P Valadão Ana-Luiza Chaves AC Robinson Kim Samirah KS Bastard Paul P Lam Nathaniel N Fadrique Ricardo R Rossi Ida I Pericat David D Bagayoko Salimata S Leon-Icaza Stephen Adonai SA Rombouts Yoann Y Perouzel Eric E Tiraby Michèle M Zhang Qian Q Cicuta Pietro P Jouanguy Emmanuelle E Neyrolles Olivier O Bryant Clare E CE Floto Andres R AR Goujon Caroline C Lei Franklin Zhong FZ Martin-Blondel Guillaume G Silva Stein S Casanova Jean-Laurent JL Cougoule Céline C Reversade Bruno B Marcoux Julien J Ravet Emmanuel E Meunier Etienne E

Molecular cell 20220516 13

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 ...[more]

PMID: 35594856

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Project description:We describe a mammalian cell-based assay to identify coronavirus 3CL protease (3CLpro) inhibitors. This assay is based on rescuing protease-mediated cytotoxicity and does not require live virus. By enabling the facile testing of compounds across a range of 15 distantly related coronavirus 3CLpro enzymes, we identified compounds with broad 3CLpro-inhibitory activity. We also adapted the assay for use in compound screening and in doing so uncovered additional severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CLpro inhibitors. We observed strong concordance between data emerging from this assay and those obtained from live-virus testing. The reported approach democratizes the testing of 3CLpro inhibitors by developing a simplified method for identifying coronavirus 3CLpro inhibitors that can be used by the majority of laboratories, rather than the few with extensive biosafety infrastructure. We identified two lead compounds, GC376 and compound 4, with broad activity against all 3CL proteases tested, including 3CLpro enzymes from understudied zoonotic coronaviruses. IMPORTANCE Multiple coronavirus pandemics have occurred over the last 2 decades. This has highlighted a need to be proactive in the development of therapeutics that can be readily deployed in the case of future coronavirus pandemics. We developed and validated a simplified cell-based assay for the identification of chemical inhibitors of 3CL proteases encoded by a wide range of coronaviruses. This assay is reporter free, does not require specialized biocontainment, and is optimized for performance in high-throughput screening. By testing reported 3CL protease inhibitors against a large collection of 3CL proteases with variable sequence similarity, we identified compounds with broad activity against 3CL proteases and uncovered structural insights into features that contribute to their broad activity. Furthermore, we demonstrated that this assay is suitable for identifying chemical inhibitors of proteases from families other than 3CL proteases.

Dataset Information

Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells.

Publications

Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells.

Similar Datasets

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