NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent release of the pro-inflammatory cytokines IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Recent studies have revealed new regulators of the NLRP3 inflammasome, including new interacting or regulatory proteins, metabolic pathways and a regulatory mitochondrial hub. In this Review, we present the molecular, cell biological and biochemical bases of NLRP3 activation and regulation and describe how this mechanistic understanding is leading to potential therapeutics that target the NLRP3 inflammasome. Full-length mouse NLRP3 is a 12- to 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 many NLRP3-activating stimuli, requires the double-ring cages of NLRP3. Double-ring-defective NLRP3 mutants abolish inflammasome punctum formation, caspase-1 processing, and cell death. Here you can see the structure of the mouse NLRP3 determined by cryoEM, showing the tightly packed dodecamer complex (PDB code: 7LFH)
#molecularart ... #immolecular ... #NLRP3 ... #sensor ... #membrane ... #dodecamer ... #motif ... #defense ... #cryoem
NLRP3 dodecamer rendered with @proteinimaging and depicted with @corelphotopaint
#molecularart ... #immolecular ... #NLRP3 ... #sensor ... #membrane ... #dodecamer ... #motif ... #defense ... #cryoem
NLRP3 dodecamer rendered with @proteinimaging and depicted with @corelphotopaint
