NACHT, LRR and PYD domains-containing protein 3 (NLRP3) (NLRP3)

NACHT, LRR and PYD domains-containing protein 3 (NLRP3) is a cytosolic pattern-recognition receptor (PRR) that serves as the sensor component of the NLRP3 inflammasome complex (UniProt Q96P20). It is the primary molecular target activated by aluminum-based vaccine adjuvants (alum), which trigger its assembly through lysosomal destabilization and the release of reactive oxygen species (Eisenbarth et al., Nature 2008). Upon activation, NLRP3 oligomerizes and recruits the adapter protein ASC and the effector protease caspase-1, leading to the proteolytic cleavage and secretion of the potent pro-inflammatory cytokines IL-1β and IL-18, as well as the induction of pyroptosis (Mangan et al., Nat Rev Drug Discov 2018). Dysregulation of the NLRP3 inflammasome is a key driver in the pathogenesis of numerous chronic inflammatory, metabolic, and neurodegenerative diseases, including gout, Type 2 diabetes, and Alzheimer's disease. As a result, NLRP3 has emerged as a high-priority therapeutic target, with several small-molecule inhibitors such as Dapansutrile and Inzomelid currently in clinical development to treat a wide range of inflammatory conditions (ClinicalTrials.gov).

Other names

CryopyrinNACHT, LRR and PYD domains-containing protein 3Caspase recruitment domain-containing protein 7CIAS1PYPAF1NALP3NLRP3 inflammasomeCLR1.1

Small molecule inhibitors typically bind to the NACHT domain of NLRP3, inhibiting its ATPase activity and preventing the conformational change required for oligomerization and inflammasome assembly, thereby blocking the maturation of pro-inflammatory cytokines IL-1β and IL-18 (Mangan et al., 2018).