NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome (NLRP3)

The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome is a tripartite cytosolic protein complex that serves as a key component of the innate immune system [1, 2]. It is composed of the NLRP3 sensor protein, the adapter protein ASC (apoptosis-associated speck-like protein containing a CARD), and the effector protease pro-caspase-1 [2]. Activation occurs in response to a diverse array of stimuli, including extracellular ATP, crystalline substances like uric acid, and protein aggregates, leading to the assembly of the complex and the activation of caspase-1 [2, 3]. Activated caspase-1 then processes the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) into their mature, secreted forms and initiates pyroptosis, a form of programmed inflammatory cell death [1, 2]. Chronic or aberrant activation of the NLRP3 inflammasome is implicated in the pathogenesis of numerous inflammatory and metabolic diseases, such as gout, type 2 diabetes, and Alzheimer's disease [2, 4]. As a result, NLRP3 has emerged as a major therapeutic target, with small-molecule inhibitors like dapansutrile and various clinical-stage candidates designed to block its activation and reduce systemic inflammation [3, 4]. Sources: [1] UniProt (P59496); [2] Nature Reviews Immunology (2019) 19:477-489; [3] Nature Reviews Drug Discovery (2018) 17:588-606; [4] PNAS (2018) 115(9):E2128-E2137.

Other names

CryopyrinCIAS1NALP3PYPAF1Caterpiller 1.1CLR1.1NACHT, LRR and PYD domains-containing protein 3

Direct inhibition of the NLRP3 NACHT domain ATPase activity, which prevents the conformational changes required for oligomerization, ASC speck formation, and subsequent inflammasome assembly.