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

Tapia-Abellán, Ana; Angosto-Bazarra, Diego; Alarcón-Vila, Cristina; Baños, María C.; Hafner-Bratkovič, Iva; Oliva Miguel, Baldomero; Pelegrín, Pablo

doi:http://dx.doi.org/10.1126/sciadv.abf4468

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

Llicència

Citació

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

Resum

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.