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

Tapia-Abellán, AnaAngosto-Bazarra, DiegoAlarcón-Vila, CristinaBaños, María C.Hafner-Bratkovič, IvaOliva Miguel, BaldomeroPelegrín, PabloPelegrín, Pablo2021-10-202021-10-202021Tapia-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.abf44682375-2548http://hdl.handle.net/10230/48714The 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.application/pdfeng© 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.Sensing low intracellular potassium by NLRP3 results in a stable open structure that promotes inflammasome activationinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1126/sciadv.abf4468info:eu-repo/semantics/openAccess