NLR family pyrin domain-containing 3 protein (NLRP3)

NLR family pyrin domain-containing 3 protein (NLRP3) is an intracellular sensor protein, predominantly expressed in immune cells such as macrophages, that acts as a central component of the NLRP3 inflammasome. Structurally, NLRP3 contains a pyrin domain (PYD), a central NACHT domain conferring ATPase activity, and a leucine-rich repeat (LRR) domain that mediates autoregulation. Upon detection of a diverse array of danger signals—including microbial motifs, extracellular ATP, uric acid crystals, and various cellular stressors—NLRP3 oligomerizes and triggers assembly of the inflammasome complex with the adapter ASC and caspase-1, leading to activation and secretion of the pro-inflammatory cytokines IL-1β and IL-18 and induction of pyroptosis. Aberrant or constitutive activation of NLRP3, often due to gain-of-function mutations, underlies several autoinflammatory diseases (collectively referred to as cryopyrin-associated periodic syndromes) and is implicated in diverse pathologies including cardiovascular, metabolic, and neurodegenerative disorders. NLRP3 is considered a high-value therapeutic target, with selective inhibitors such as MCC950 and dapansutrile in clinical development for inflammatory and autoimmune conditions.

Other names

NACHT, LRR, and PYD domains-containing protein 3NALP3CryopyrinCold induced autoinflammatory syndrome 1 (CIAS1)Caterpillar-like receptor 1.1 (CLR1.1)PYRIN-containing APAF1-like protein 1 (PYPAF1)

Inhibition of NLRP3 inflammasome assembly and activation; Inhibition of ATPase activity in the NACHT domain; Disruption of oligomerization and ASC speck formation; Blocking caspase-1 activation and cytokine release