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

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

  • Mol Cell. 2022 Jul 7;82(13):2385-2400.e9. doi: 10.1016/j.molcel.2022.04.033.
Rémi Planès 1,  Miriam Pinilla 2,  Karin Santoni 3,  Audrey Hessel 3,  Charlotte Passemar 4,  Kenneth Lay 5,  Perrine Paillette 6,  Ana-Luiza Chaves Valadão 7,  Kim Samirah Robinson 8,  Paul Bastard 9,  Nathaniel Lam 10,  Ricardo Fadrique 11,  Ida Rossi 3,  David Pericat 3,  Salimata Bagayoko 3,  Stephen Adonai Leon-Icaza 3,  Yoann Rombouts 3,  Eric Perouzel 6,  Michèle Tiraby 6,  COVID Human Genetic Effort,  Qian Zhang 12,  Pietro Cicuta 11,  Emmanuelle Jouanguy 9,  Olivier Neyrolles 3,  Clare E Bryant 10,  Andres R Floto 4,  Caroline Goujon 7,  Franklin Zhong Lei 13,  Guillaume Martin-Blondel 14,  Stein Silva 15,  Jean-Laurent Casanova 16,  Céline Cougoule 3,  Bruno Reversade 17,  Julien Marcoux 3,  Emmanuel Ravet 6,  Etienne Meunier 18
Affiliations

Affiliations

  • 1 Institute of Pharmacology and Structural Biology (IPBS), University of Toulouse, CNRS, Toulouse, France; InvivoGen, Toulouse, France; IRIM, University of Montpellier, CNRS, Montpellier, France. Electronic address: remi.planes@ipbs.fr.
  • 2 Institute of Pharmacology and Structural Biology (IPBS), University of Toulouse, CNRS, Toulouse, France; InvivoGen, Toulouse, France.
  • 3 Institute of Pharmacology and Structural Biology (IPBS), University of Toulouse, CNRS, Toulouse, France.
  • 4 Molecular Immunity Unit, University of Cambridge Department of Medicine, MRC-Laboratory of Molecular Biology, Cambridge, UK.
  • 5 Institute of Medical Biology, Agency of Science, Technology and Research, 8A Biomedical Grove, #06-06 Immunos, 138648 Singapore, Singapore; Laboratory of Human Genetics and Therapeutics, Genome Institute of Singapore (GIS), A(∗)STAR, Singapore, Singapore.
  • 6 InvivoGen, Toulouse, France.
  • 7 IRIM, University of Montpellier, CNRS, Montpellier, France.
  • 8 A(∗)STAR Skin Research Laboratories, 11 Mandalay Road, 308232 Singapore, Singapore.
  • 9 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, Necker Hospital for Sick Children, Paris, France; University of Paris, Imagine Institute, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
  • 10 University of Cambridge, Department of Veterinary Medicine, Cambridge CB30ES, UK; University of Cambridge, School of Clinical Medicine, Box 111, Cambridge Biomedical Campus, Cambridge CB2 0SP, UK.
  • 11 Biological and Soft Systems, Cavendish Laboratory, University of Cambridge, JJ Thomson Avenue, Cambridge CB3 0HE, UK.
  • 12 University of Paris, Imagine Institute, Paris, France.
  • 13 A(∗)STAR Skin Research Laboratories, 11 Mandalay Road, 308232 Singapore, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, 308232 Singapore, Singapore; Skin Research Institute of Singapore (SRIS), 11 Mandalay Road, 308232 Singapore, Singapore.
  • 14 Service des Maladies Infectieuses et Tropicales, CHU de Toulouse, Toulouse, France; Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), INSERM UMR1291 - CNRS UMR5051 - Université Toulouse III, Toulouse, France.
  • 15 Critical Care Unit, University Hospital of Purpan, Toulouse, France.
  • 16 Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U1163, Necker Hospital for Sick Children, Paris, France; University of Paris, Imagine Institute, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA; Howard Hughes Medical Institute, New York, NY, USA.
  • 17 Institute of Medical Biology, Agency of Science, Technology and Research, 8A Biomedical Grove, #06-06 Immunos, 138648 Singapore, Singapore; Laboratory of Human Genetics and Therapeutics, Genome Institute of Singapore (GIS), A(∗)STAR, Singapore, Singapore; Institute of Molecular and Cell Biology, 61 Biopolis Drive, 138673 Singapore, Singapore; Department of Paediatrics, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 10 Medical Drive, 117597 Singapore, Singapore; The Medical Genetics Department, Koç University School of Medicine, 34010 Istanbul, Turkey.
  • 18 Institute of Pharmacology and Structural Biology (IPBS), University of Toulouse, CNRS, Toulouse, France. Electronic address: etienne.meunier@ipbs.fr.
PMID: 35594856 DOI: 10.1016/j.molcel.2022.04.033
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.

Keywords

3CL proteases; Gasdermins; NLRP1 inflammasome; SARS-CoV-2; epithelial cells; pyroptosis.

Figures