RT Journal Article
SR Electronic
T1 Full-length NLRP3 forms oligomeric cages to mediate NLRP3 sensing and activation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.09.12.459968
DO 10.1101/2021.09.12.459968
A1 Liudmila Andreeva
A1 Liron David
A1 Shaun Rawson
A1 Chen Shen
A1 Teerithveen Pasricha
A1 Pablo Pelegrin
A1 Hao Wu
YR 2021
UL http://biorxiv.org/content/early/2021/09/12/2021.09.12.459968.abstract
AB The nucleotide-binding domain and leucine-rich-repeat (LRR) containing protein 3 with a pyrin domain (NLRP3) is emerging to be a critical intracellular inflammasome sensor of membrane integrity and a highly important clinical target against chronic inflammation. Here we report that the endogenous, stimulus-responsive form of full-length NLRP3 is a 12-16 mer double ring cage held together by LRR-LRR interactions with the pyrin domains shielded within the assembly to avoid premature activation. Surprisingly, this NLRP3 form is predominantly membrane localized, which is consistent with previously noted localization of NLRP3 at various membrane organelles. Structure-guided mutagenesis reveals that trans-Golgi network dispersion into vesicles, an early event observed for all NLRP3 activating stimuli, requires the double ring cages of NLRP3. Double ring-defective NLRP3 mutants further abolish inflammasome punctum formation, caspase-1 processing and cell death. Thus, unlike other inflammasome sensors that are monomeric when inactive, our data uncover a unique NLRP3 oligomer on membrane that is poised to sense diverse signals to induce inflammasome activation.Competing Interest StatementH.W. is a co-founder of Ventus Therapeutics. The other authors declare no competing interests.