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

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2021 Potassium.pdf(10.24 MB)
Date
2021-09-15
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Authors
Angosto-Bazarra, Diego ; Alarcón-Vila, Cristina ; Baños, Maria C ; Hafner-Bratkovič, Iva ; Oliva, Baldomero ; Pelegrín Vivancos, Pablo ; Tapia Abellán, Ana
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Publisher
American Association for the Advancement of Science
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Bioquímica y Biología Molecular B e Inmunología
DOI
https://doi.org/10.1126/sciadv.abf4468
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info:eu-repo/semantics/article
Description
© 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. 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 Science Advances. To access the final edited and published work see https://doi.org/10.1126/sciadv.abf4468
Abstract
The NLRP3 inflammasome is activated in response to 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 different 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 presence of the specific NLRP3 FISNA domain and a unique flexible linker sequence between the PYD and FISNA domains. This linker is also important to facilitate 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 N-terminal sequence between PYD and NACHT domain of NLRP3 is key for inflammasome activation.
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Inflammasome , Inflammation , NLRP3
Citation
Science Advances, 2021, Vol. 7, Issue 38 : eabf4468
URI
http://hdl.handle.net/10201/148842
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