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.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.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.doi http://dx.doi.org/10.1126/sciadv.abf4468
  • dc.identifier.issn 2375-2548
  • dc.identifier.uri http://hdl.handle.net/10230/48714
  • dc.language.iso eng
  • dc.publisher American Association for the Advancement of Science (AAAS)
  • dc.relation.ispartof Sci Adv. 2021;7(38):eabf4468
  • 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 © 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.accessRights info:eu-repo/semantics/openAccess
  • 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.type.version info:eu-repo/semantics/publishedVersion

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