ArticleThe Journal of experimental medicine2024
Functional diversity of NLRP3 gain-of-function mutants associated with CAPS autoinflammation.
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Article in The Journal of experimental medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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30 citing papers in PubMed, 38 citations in OpenAlex.
- Pyroptotic cell-derived factors promote osteoclast differentiation.bioRxiv : the preprint server for biology · 2026Article
- Innate immunity: current understandings and future perspectives.Signal transduction and targeted therapy · 2026Review
- Decoding variants of uncertain significance in systemic autoinflammatory diseases.Nature reviews. Rheumatology · 2026Review
- Pharmacological targeting of the NLRP3 LRR domain with isothiazolinones overcomes CRID3-resistant inflammation.EMBO molecular medicine · 2026Article
- Cofilin-1 is a redox-sensitive guard of the NLRP3 inflammasome.Nature immunology · 2026Article
- Targeting CD177: A Novel Therapeutic Strategy for NLRP3-Associated Autoinflammatory Diseases.International journal of molecular sciences · 2026Article
- Mice humanized by syntenic replacement with full-length NLRP3 disease-associated variants model the clinical cryopyrinopathy continuum.JCI insight · 2026Article
- The NLRP3 Inflammasome: Mechanisms of Activation, Regulation, and Therapeutic Opportunities.MedComm · 2026Review
- Diverse Scaffolds Facilitate NLRP3 Clustering and Inflammasome Formation in Response to Perturbations in Cell Homeostasis.BioEssays : news and reviews in molecular, cellular and developmental biology · 2026Review
- The Crohn's disease-related RNF123 prevents NLRP3 inflammasome assembly by catalyzing unanchored K63-linked ubiquitination on NEK7.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- CNS-targeted NLRP3 Inhibition by NT-0527 confers therapeutic advantage in a CAPS mouse model.Journal of neuroinflammation · 2026Article
- Post-translational modifications of NLRP3: to prime or not to prime?Trends in immunology · 2026Review
- Recent variant discoveries and emerging genetic mechanisms in autoinflammatory diseases.Frontiers in immunology · 2026Review
- Discovery of potent and selective inhibitors of human NLRP3 with a novel mechanism of action.The Journal of experimental medicine · 2025Article
- Update on new autoinflammatory disorders from the 2024 Pediatric Rheumatology European Society Congress.Pediatric rheumatology online journal · 2025Review
- Novel Insights into the Clinical Features, Genetic Spectrum and Clonal Evolution of Patients Carrying NLRP3 Mosaicism.Journal of clinical immunology · 2025Article
- Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) Syndrome in Children-From Pathogenesis to Treatment Strategies: A Comprehensive Review.Paediatric drugs · 2025Review
- The expanding role of the NLRP3 inflammasome from periodic fevers to therapeutic targets.Nature immunology · 2025Review
- Targeting the NLRP3 inflammasome for inflammatory disease therapy.Trends in pharmacological sciences · 2025Review
- Clustering of NLRP3 induced by membrane or protein scaffolds promotes inflammasome assembly.Nature communications · 2025Article
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Authors and funding
36 authors at 16 institutions in 3 countries.
Camille Cosson *CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308 , ENS de Lyon, Lyon, France.ORCID 0000-0002-7402-457X
Romane Riou *CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308 , ENS de Lyon, Lyon, France.ORCID 0000-0002-2345-8503
Danish PatoliCIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308 , ENS de Lyon, Lyon, France.ORCID 0000-0002-6837-336X
Tingting NiuCIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308 , ENS de Lyon, Lyon, France.ORCID 0000-0002-8876-1925
Amaury ReyCIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308 , ENS de Lyon, Lyon, France.ORCID 0000-0002-6355-7119
Marine GroslambertCIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308 , ENS de Lyon, Lyon, France.ORCID 0000-0003-3258-0268
Charlotte De RosnyCIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308 , ENS de Lyon, Lyon, France.ORCID 0000-0002-4153-1399
Elodie ChatreUniv Lyon, ENS de Lyon, Inserm, CNRS SFR Biosciences US8 UAR3444, Université Claude Bernard Lyon 1 , Lyon, France.ORCID 0009-0001-9430-6451
Omran AllatifCIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308 , ENS de Lyon, Lyon, France.ORCID 0000-0002-2539-972X
Thomas HenryCIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308 , ENS de Lyon, Lyon, France.ORCID 0000-0002-0687-8565
Fabienne VenetCIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308 , ENS de Lyon, Lyon, France.ORCID 0000-0003-0462-4235
Florian MilhavetInstitute for Regenerative Medicine and Biotherapy, Inserm, U1183, University of Montpellier , Montpellier, France.ORCID 0009-0000-0779-8121
Guilaine BoursierInstitute for Regenerative Medicine and Biotherapy, Inserm, U1183, University of Montpellier , Montpellier, France.ORCID 0000-0002-2903-3135
Alexandre BelotCIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308 , ENS de Lyon, Lyon, France.ORCID 0000-0003-4902-5332
Yvan JamillouxCIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308 , ENS de Lyon, Lyon, France.
Etienne MerlinDepartment of Pediatrics, Clermont-Ferrand University Hospital, Clermont-Ferrand, France.ORCID 0000-0001-6527-7893
Agnès DuquesneCentre de Référence des Maladies Autoinflammatoires et des Amyloses Inflammatoires, CEREMAIA , France.ORCID 0000-0002-8288-3411
Gilles GrateauCentre de Référence des Maladies Autoinflammatoires et des Amyloses Inflammatoires, CEREMAIA , France.
Léa SaveyCentre de Référence des Maladies Autoinflammatoires et des Amyloses Inflammatoires, CEREMAIA , France.ORCID 0000-0002-1989-1304
Alexandre Thibault Jacques MariaInternal Medicine and Onco-Immunology (MedI2O), Institute for Regenerative Medicine and Biotherapy (IRMB), Saint Eloi Hospital, Montpellier University , Montpellier, France.ORCID 0000-0002-0868-5804
Anne PagnierCentre Hospitalier Universitaire Grenoble Alpes, Immunologie Clinique, Immuno-Hémato-Oncologie (IHO), Hôpital Couple-Enfant , Grenoble, France.ORCID 0000-0002-3981-8331
Solène PoutrelService de Médecine Interne, Hospices Civils de Lyon, Edouard Herriot Hospital , Lyon, France.ORCID 0009-0005-2903-8701
Olivier LambotteAssistance Publique-Hôpitaux de Paris, Service de Médecine Interne et Immunologie Clinique, Groupe Hospitalier Universitaire Paris Saclay, Hôpital Bicêtre , Le Kremlin-Bicêtre, France.ORCID 0000-0003-4425-8516
Coralie MallebrancheUniversité d'Angers, Université de Nantes, Inserm, CNRS, CRCI2NA, SFR ICAT, Angers, France.ORCID 0000-0002-8385-4057
Samuel ArdoisMédecine Interne et Immunologie Clinique , Centre Hospitalier Universitaire de Rennes, Rennes, France.ORCID 0009-0009-9631-4445
Olivier RicherPaediatric, Rheumatology and Paediatric Internal Medicine, Reference Center for Rheumatic, Autoimmune and Systemic Diseases in Children (RAISE), Children's Hospital , Bordeaux, France.ORCID 0000-0003-4863-2982
Irène LemelleDepartment of Pediatric Onco-hematology, Children Hospital, University Hospital of Nancy, Lorraine University, Vandoeuvre-lès-Nancy, France.ORCID 0000-0002-8761-2020
Frédéric Rieux-LaucatUniversité Paris Cité, Institut Imagine, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Inserm UMR 1163 , Paris, France.ORCID 0000-0001-7858-7866
Brigitte Bader-MeunierUniversité Paris Cité, Institut Imagine, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Inserm UMR 1163 , Paris, France.ORCID 0000-0001-8476-8196
Zahir AmouraAssistance Publique-Hôpitaux de Paris (AP-HP)-Sorbonne Université, Hopital Pitié-Salpétrière, Institut E3M, Service de Médecine Interne 2, Centre National de Référence Lupus et Syndrome des Anticorps Antiphospholipides, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Paris, France.ORCID 0000-0003-0292-9043
Isabelle MelkiPaediatric, Rheumatology and Paediatric Internal Medicine, Reference Center for Rheumatic, Autoimmune and Systemic Diseases in Children (RAISE), Children's Hospital , Bordeaux, France.ORCID 0000-0002-8057-333X
Laurence CuissetUniversité Paris Cité, Service de Médecine Génomique des Maladies de Système et D'Organe, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris , Paris, France.ORCID 0000-0003-4007-3629
Isabelle TouitouInstitute for Regenerative Medicine and Biotherapy, Inserm, U1183, University of Montpellier , Montpellier, France.ORCID 0000-0002-5171-1000
Matthias GeyerInstitute of Structural Biology, University of Bonn , Bonn, Germany.ORCID 0000-0002-7718-5002
Sophie Georgin-LavialleCentre de Référence des Maladies Autoinflammatoires et des Amyloses Inflammatoires, CEREMAIA , France.ORCID 0000-0001-6668-8854
Bénédicte F PyCIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308 , ENS de Lyon, Lyon, France.ORCID 0000-0001-6716-7807
Université Claude Bernard Lyon 1 · FRInserm · FRUniversité Paris-Saclay · FRAssistance Publique – Hôpitaux de Paris · FRCentre Hospitalier Universitaire de Clermont-Ferrand · FRCentre Hospitalier Universitaire de Rennes · FRCentre National de la Recherche Scientifique · FRHôpital Couple Enfant · FRHôpital Femme Mère Enfant · FRHôpital Necker-Enfants Malades · FRHospices Civils de Lyon · FRSorbonne Université · FRUniversité de Lorraine · FRUniversité de Montpellier · FRUniversité Paris Cité · FRUniversity of Bonn · DE
Funding
European Research Council ERC-2013-CoG_616986
Abstract
NLRP3-associated autoinflammatory disease is a heterogenous group of monogenic conditions caused by NLRP3 gain-of-function mutations. The poor functional characterization of most NLRP3 variants hinders diagnosis despite efficient anti-IL-1 treatments. Additionally, while NLRP3 is controlled by priming and activation signals, gain-of-functions have only been investigated in response to priming. Here, we characterize 34 NLRP3 variants in vitro, evaluating their activity upon induction, priming, and/or activation signals, and their sensitivity to four inhibitors. We highlight the functional diversity of the gain-of-function mutants and describe four groups based on the signals governing their activation, correlating partly with the symptom severity. We identify a new group of NLRP3 mutants responding to the activation signal without priming, associated with frequent misdiagnoses. Our results identify key NLRP3 residues controlling inflammasome activity and sensitivity to inhibitors, and antagonistic mechanisms with broader efficacy for therapeutic strategies. They provide new insights into NLRP3 activation, an explanatory mechanism for NLRP3-AID heterogeneity, and original tools for NLRP3-AID diagnosis and drug development.
Indexed as
Gain of Function MutationNLR Family, Pyrin Domain-Containing 3 ProteinDrug DevelopmentHumansInflammasomesSyndromeInflammasomesNLR Family, Pyrin Domain-Containing 3 Protein
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