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 |