NLRP3

NLRP3 (cryopyrin) is a cytosolic NLR-family protein of myeloid and other innate immune cells that nucleates the NLRP3 inflammasome, the platform that activates caspase-1 and so drives maturation of interleukin-1 beta and interleukin-18 and gasdermin-D-dependent pyroptosis. It is built from an N-terminal pyrin domain, a central nucleotide-binding NACHT domain and a C-terminal leucine-rich repeat. In the resting state it is held as an autoinhibited, ADP-bound, membrane-binding oligomeric cage - reported as a decamer and as a dodecamer by different groups - with the pyrin domains sequestered inside the leucine-rich-repeat shell. Activation converts the NACHT domain to an ATP-bound conformation and assembles an active disc in which the pyrin domains stack into a filament that nucleates unidirectional polymerisation of the adaptor ASC, which in turn recruits procaspase-1. NLRP3 has no established direct agonist ligand. It responds to an unusually wide range of stimuli - pore-forming toxins, extracellular ATP, crystals such as monosodium urate, silica and alum, cell swelling, and mitochondrial and lysosomal damage - and the prevailing view is that it detects a shared downstream cellular perturbation, with potassium efflux and disassembly of the trans-Golgi network as common intermediates, rather than binding each agonist. Recruitment to the dispersed trans-Golgi network occurs through ionic interaction between a conserved polybasic region and phosphatidylinositol-4-phosphate, after which microtubule-dependent transport concentrates NLRP3, together with the kinase NEK7, as condensates at the pericentriolar material of the microtubule organising centre. Whether this route is obligatory is disputed: low-molecular-weight, non-cage NLRP3 species can drive a slower, trans-Golgi- and MTOC-distal pathway that dominates in human neutrophils, and raising NLRP3 abundance can make potassium-efflux-driven activation independent of both NEK7 and priming. Gain-of-function mutations, mostly in the NACHT-encoding exon 3, cause the cryopyrin-associated periodic syndromes - familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal-onset multisystem inflammatory disease - which respond to interleukin-1 blockade, and NLRP3 activity contributes to gout, atherosclerosis, silicosis and neuroinflammation. A separate, inflammasome-independent role for NLRP3 as a nuclear transcriptional cofactor that binds the Il4 promoter with IRF4 in T helper 2 cells has been reported in mouse but is not independently corroborated.

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

• neuroinflammation_glial_activation via Alzheimer Disease
• nlrp3_inflammasome_activation via Familial Cold Autoinflammatory Syndrome, Multiple Sclerosis