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Sensing low intracellular potassium by NLRP3 results in a stable open structure that promotes inflammasome activation

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dc.contributor.author Tapia-Abellán, Ana
dc.contributor.author Angosto-Bazarra, Diego
dc.contributor.author Alarcón-Vila, Cristina
dc.contributor.author Baños, María C.
dc.contributor.author Hafner-Bratkovič, Iva
dc.contributor.author Oliva Miguel, Baldomero
dc.contributor.author Pelegrín, Pablo
dc.contributor.author Pelegrín, Pablo
dc.date.accessioned 2021-10-20T06:29:27Z
dc.date.available 2021-10-20T06:29:27Z
dc.date.issued 2021
dc.identifier.citation Tapia-Abellán A, Angosto-Bazarra D, Alarcón-Vila C, Baños MC, Hafner-Bratkovič I, Oliva B, Pelegrín P. Sensing low intracellular potassium by NLRP3 results in a stable open structure that promotes inflammasome activation. Sci Adv. 2021;7(38):eabf4468. DOI: 10.1126/sciadv.abf4468
dc.identifier.issn 2375-2548
dc.identifier.uri http://hdl.handle.net/10230/48714
dc.description.abstract The NLRP3 inflammasome is activated by a wide range of stimuli and drives diverse inflammatory diseases. The decrease of intracellular K+ concentration is a minimal upstream signal to most of the NLRP3 activation models. Here, we found that cellular K+ efflux induces a stable structural change in the inactive NLRP3, promoting an open conformation as a step preceding activation. This conformational change is facilitated by the specific NLRP3 FISNA domain and a unique flexible linker sequence between the PYD and FISNA domains. This linker also facilitates the ensemble of NLRP3PYD into a seed structure for ASC oligomerization. The introduction of the NLRP3 PYD-linker-FISNA sequence into NLRP6 resulted in a chimeric receptor able to be activated by K+ efflux–specific NLRP3 activators and promoted an in vivo inflammatory response to uric acid crystals. Our results establish that the amino-terminal sequence between PYD and NACHT domain of NLRP3 is key for inflammasome activation.
dc.description.sponsorship I.H.-B. would like to acknowledge the funding by the Slovenian Research Agency (project grant J3-1746 and core funding P4-0176), and B.O. would like to acknowledge the funding by the Ministerio de Economía, Industria y Competitividad and ERDF (BIO2017-85329-R). This work was supported by grants to A.T.-A. from the internal support program of the Medical Faculty, University of Tübingen, Fortüne-Antrag Nr. 2615-0-0 and to P.P. from FEDER/Ministerio de Ciencia, Innovación y Universidades—Agencia Estatal de Investigación (grant SAF2017-88276-R), Fundación Séneca (grants 20859/PI/18, 21081/PDC/19, and 0003/COVI/20), and the European Research Council (ERC-2013-CoG grant 614578 and ERC-2019-PoC grant 899636).
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher American Association for the Advancement of Science (AAAS)
dc.relation.ispartof Sci Adv. 2021;7(38):eabf4468
dc.rights © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
dc.rights.uri https://creativecommons.org/licenses/by-nc/4.0/
dc.title Sensing low intracellular potassium by NLRP3 results in a stable open structure that promotes inflammasome activation
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1126/sciadv.abf4468
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/614578
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/899636
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BIO2017-85329-R
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017-88276-R
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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