Sensing low intracellular potassium by NLRP3 results in a stable open structure that promotes inflammasome activation.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 34524838.
- Also identified by DOI 10.1126/sciadv.abf4468 and PMC identifier 8443177.
- Licence recorded as CC BY-NC.
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Abstract
The NLRP3 inflammasome is activated by a wide range of stimuli and drives diverse inflammatory diseases. The decrease of intracellular K<sup>+</sup> concentration is a minimal upstream signal to most of the NLRP3 activation models. Here, we found that cellular K<sup>+</sup> 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<sup>PYD</sup> 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<sup>+</sup> 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.