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

Autor: Tapia-Abellán A; Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, 30120 Murcia, Spain.; Interfaculty Institute for Cell Biology, Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, 72076 Tübingen, Germany., Angosto-Bazarra D; Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, 30120 Murcia, Spain., Alarcón-Vila C; Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, 30120 Murcia, Spain., Baños MC; Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, 30120 Murcia, Spain., Hafner-Bratkovič I; Department of Synthetic Biology and Immunology, National Institute of Chemistry, EN-FIST Centre of Excellence, Ljubljana, Slovenia., Oliva B; Laboratory of Structural Bioinformatics (GRIB), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona 08003, Spain., Pelegrín P; Instituto Murciano de Investigación Biosanitaria IMIB-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, 30120 Murcia, Spain.; Department of Biochemistry and Molecular Biology B and Immunology, Faculty of Medicine, University of Murcia, 30120 Murcia, Spain.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2021 Sep 17; Vol. 7 (38), pp. eabf4468. Date of Electronic Publication: 2021 Sep 15.
DOI: 10.1126/sciadv.abf4468
Abstrakt: 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 NLRP3 PYD 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.
Databáze: MEDLINE
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