Figure 1.
(a) NLRP3 domains. (b) The sensor-adaptor-effector machinery of the NLRP3 inflammasome, depicting interaction of NLRP3 with ASC through their PYDs, and interaction of ASC with caspase-1 through their CARDs. (c) A molecular model of the NLRP3 inflammasome pathway, stepwise from upstream (❶) to downstream (❽). NLRP3 conformational change and the subsequent intracellular trafficking lead to the binding of NLRP3 to NEK7, which induces formation of an NLRP3 inflammasome disk and promotes NLRP3 PYD to form a filament. The NLRP3 PYD filament recruits ASC by nucleating the ASC PYD filament. The CARD of ASC also clusters and forms a filament. The ASC CARD filament recruits caspase-1 by nucleating the caspase-1 CARD filament. The caspase-1 caspase domain (p20/p10) dimerizes and autoprocesses, resulting in its activation. The active caspase-1 then cleaves pro-cytokines in the IL-1 family to generate mature cytokines. Caspase-1 also cleaves GSDMD to generate an active GSDMD N-terminal fragment for membrane pore formation that facilitates cytokine release and pyroptosis. Abbreviations: ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; CARD, C-terminal caspase recruitment domain; FISNA, fish-specific NACHT-associated domain; GSDMD, gasdermin D; HD1, helical domain 1; LRR, leucine-rich repeat; NBD, nucleotide-binding domain; NEK7, NIMA-related kinase 7; PYD, pyrin domain; WHD, winged helix domain.