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Pathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β production

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dc.contributor.authorMolina-López, Cristina
dc.contributor.authorHurtado-Navarro, Laura
dc.contributor.authorGarcia, Carlos J.
dc.contributor.authorAngosto-Bazarra, Diego
dc.contributor.authorVallejo, Fernando
dc.contributor.authorMarques-Soares, Joana R.
dc.contributor.authorVargas, Carmen
dc.contributor.authorBujan-Rivas, Segundo
dc.contributor.authorTomás-Barberán, Francisco A.
dc.contributor.authorArostegui, Juan I.
dc.contributor.authorPelegrín Vivancos, Pablo
dc.contributor.authorTapia Abellán, Ana
dc.contributor.departmentBioquímica y Biología Molecular B e Inmunología
dc.date.accessioned2025-01-20T13:05:04Z
dc.date.available2025-01-20T13:05:04Z
dc.date.issued2024-02-06
dc.description© 2024, The Author(s). This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ This document is the Accepted Manuscript version of a Published Work that appeared in final form in Nature Communications. To access the final edited and published work see https://doi.org/10.1038/s41467-024-44990-0es
dc.description.abstractCryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory condition resulting from monoallelic NLRP3 variants that facilitate IL-1b production. Although these are gain-of-function variants characterised by hypersensitivity to cell priming, patients with CAPS and animal models of the disease may present inflammatory flares without identifiable external triggers. Here we find that CAPS-associated NLRP3 variants are forming constitutively active inflammasome, which induce increased basal cleavage of gasdermin D, IL-18 release and pyroptosis, with a concurrent basal pro-inflammatory gene expression signature, including the induction of nuclear receptors 4A. The constitutively active NLRP3-inflammasome is responsive to the selective NLRP3 inflammasome inhibitor MCC950 and its activation is regulated by deubiquitination. Despite their preactivated state, the CAPS inflammasomes are responsive to activation of the NF-kB pathway. NLRP3-inflammasomes with CAPS-associated variants affect the immunometabolism of the myeloid compartment, leading to disruptions in lipids and amino acid pathways and impaired glycolysis, limiting IL-1b production. In summary, NLRP3 variants causing CAPS form a constitutively active inflammasome inducing pyroptosis and IL-18 release without cell priming, which enables the host's innate defence against pathogens while also limiting IL-1b–dependent inflammatory episodes through immunometabolism modulation.es
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dc.format.extent81es
dc.identifier.citationNature Communications, 2024, Vol. 15 : 1096
dc.identifier.doihttps://doi.org/10.1038/s41467-024-44990-0
dc.identifier.issnElectronic: 2041-1723
dc.identifier.urihttp://hdl.handle.net/10201/148839
dc.languageenges
dc.publisherNature Researches
dc.relationThis work was supported by grants from MCIN/AEI/10.13039/501100011033 (grants PID2020-116709RB-I00, BG20/00060, CNS2022-135101 and RED2022-134511-T to PP), FEDER/Ministerio de Ciencia, Innovación y Universidades – Agencia Estatal de Investigación (grant SAF2017‐88276‐R to PP), Fundación Séneca (grants 20859/PI/18 and 21897/PI/22 to PP), the Instituto Salud Carlos III (grants DTS21/00080 and AC22/00009 to PP), the EU Horizon 2020 project PlasticHeal (grant 965196 to PP), the Spanish Ministry of Science, Innovation and Universities co-funded by the European Regional Development Fund / Agencia Estatal de Investigación (grant RTI2018-096824-B-C21 to JIA) and the Spanish Ministry of Science and Innovation / Agencia Estatal de Investigación (grant PID2021-125106OB-C31 to JIA). L.H-N. was supported by the fellowship 21214/FPI/19 (Fundación Séneca, Región de Murcia, Spain) and CM-L by was funded by the fellowship PRE2018-086824 (Ministerio economía y competitividad).es
dc.relation.publisherversionhttps://www.nature.com/articles/s41467-024-44990-0
dc.rightsinfo:eu-repo/semantics/openAccesses
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectAutoinflammatory diseasees
dc.subjectCAPSes
dc.subjectInflammasomees
dc.subjectDeubiquitinationes
dc.subjectGlycolysises
dc.subject.otherCDU::6 - Ciencias aplicadas::61 - Medicina::616 - Patología. Medicina clínica. Oncología::616.4 - Patología del sistema linfático, órganos hematopoyéticos, endocrinoses
dc.titlePathogenic NLRP3 mutants form constitutively active inflammasomes resulting in immune-metabolic limitation of IL-1β productiones
dc.typeinfo:eu-repo/semantics/articlees
dspace.entity.typePublicationes
relation.isAuthorOfPublication547c4c2c-d906-4e1d-ae9a-0cdb40eef6d1
relation.isAuthorOfPublication0ef289d2-ad85-4d81-a66c-82879daf26a9
relation.isAuthorOfPublication.latestForDiscovery547c4c2c-d906-4e1d-ae9a-0cdb40eef6d1
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