NLRP3

Up-regulated during CD4(+) T-lymphocyte differentiation, in Th0, Th1 and Th2 cells. Not detected in naive CD4(+) T-lymphocytes (at protein level).

The pyrin domain (also called DAPIN domain or PYD) is involved in PYCARD/ASC-binding.

The FISNA domain is a critical mediator of NLRP3 conformational during NLRP3 activation. It becomes ordered in its key regions during activation to stabilize the active NACHT conformation and mediate most interactions in the NLRP3 disk.

The LRR domain mediates the interaction with IRF4, PML, NEK7 and NR4A1/Nur77.

The KFERQ-like motifs mediate binding to HSPA8/HSC70 following NLRP3 paylmitoylation by ZDHHC12.

Sensor component of the NLRP3 inflammasome, which mediates inflammasome activation in response to defects in membrane integrity, leading to secretion of inflammatory cytokines IL1B and IL18 and pyroptosis (PubMed:19362020, PubMed:23582325, PubMed:26642356, PubMed:26814970, PubMed:27374331, PubMed:27929086, PubMed:28656979, PubMed:28847925, PubMed:30518920, PubMed:36178239). In response to pathogens and other damage-associated signals that affect the integrity of membranes, initiates the formation of the inflammasome polymeric complex composed of NLRP3, CASP1 and PYCARD/ASC (PubMed:16407889, PubMed:18403674, PubMed:19362020, PubMed:26642356, PubMed:26814970, PubMed:27374331, PubMed:28847925). Recruitment of pro-caspase-1 (proCASP1) to the NLRP3 inflammasome promotes caspase-1 (CASP1) activation, which subsequently cleaves and activates inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD), promoting cytokine secretion and pyroptosis (PubMed:16546100, PubMed:17008311, PubMed:26642356, PubMed:26814970, PubMed:27374331, PubMed:28847925). Activation of NLRP3 inflammasome is also required for HMGB1 secretion; stimulating inflammatory responses (PubMed:22801494). Under resting conditions, ADP-bound NLRP3 is autoinhibited (By similarity). NLRP3 activation stimuli include extracellular ATP, nigericin, reactive oxygen species, crystals of monosodium urate or cholesterol, amyloid-beta fibers, environmental or industrial particles and nanoparticles, such as asbestos, silica, aluminum salts, cytosolic dsRNA, etc (PubMed:16407888, PubMed:16407889, PubMed:16407890, PubMed:18403674, PubMed:19362020, PubMed:37001519). Almost all stimuli trigger intracellular K(+) efflux (PubMed:23809161). These stimuli lead to membrane perturbation and activation of NLRP3 (By similarity). Upon activation, NLRP3 is transported to microtubule organizing center (MTOC), where it is unlocked by NEK7, leading to its relocalization to dispersed trans-Golgi network (dTGN) vesicle membranes and formation of an active inflammasome complex (PubMed:26814970, PubMed:34615873, PubMed:34861190). Associates with dTGN vesicle membranes by binding to phosphatidylinositol 4-phosphate (PtdIns4P) (PubMed:30487600). Shows ATPase activity (PubMed:34861190).

Independently of inflammasome activation, regulates the differentiation of T helper 2 (Th2) cells and has a role in Th2 cell-dependent asthma and tumor growth (PubMed:26098997). During Th2 differentiation, required for optimal IRF4 binding to IL4 promoter and for IRF4-dependent IL4 transcription (PubMed:26098997). Binds to the consensus DNA sequence 5'-GRRGGNRGAG-3' (PubMed:26098997). May also participate in the transcription of IL5, IL13, GATA3, CCR3, CCR4 and MAF (PubMed:26098997).

Phosphorylation at Ser-194 by MAPK8/JNK1 increases inflammasome activation by promoting deubiquitination by BRCC3 and NLRP3 homooligomerization (PubMed:28943315). Phosphorylation at Ser-803 by CSNK1A1 prevents inflammasome activation by preventing NEK7 recruitment (PubMed:34615873). Phosphorylation at Ser-3 in the pyrin domain inhibits homomultimerization of NLRP3 and activation of the NLRP3 inflammasome: dephosphorylation by protein phosphatase 2A (PP2A) promotes assembly of the NLRP3 inflammasome (PubMed:28465465). Phosphorylation at Ser-291 by PKD/PRKD1 promotes NLRP3 inflammasome assembly (PubMed:28716882). Phosphorylation by ERK1/MAPK3 promotes NLRP3 inflammasome assembly (By similarity). Phosphorylation by BTK (at Tyr-132, Tyr-136, Tyr-145 and Tyr-164) in the region that mediates binding to phosphatidylinositol phosphate, promotes relocalization of NLRP3 and assembly of the NLRP3 inflammasome (PubMed:34554188). Phosphorylation at Tyr-858 inhibits NLRP3 inflammasome assembly: dephosphorylation by PTPN22 promotes inflammasome activation (PubMed:27043286).

Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination (PubMed:23246432). Ubiquitination does not lead to degradation, but inhibits inflammasome activation (PubMed:23246432). Deubiquitination is catalyzed by BRCC3 and associated with NLRP3 activation and inflammasome assembly (PubMed:23246432). This process can be induced by the activation of Toll-like receptors (by LPS), through a non-transcriptional pathway dependent on the mitochondrial production of reactive oxygen species, and by ATP (PubMed:22948162). Ubiquitinated by TRIM31 via 'Lys-48'-linked ubiquitination, leading to its degradation by the proteasome (PubMed:27929086). Ubiquitinated at Lys-687 by the SCF(FBXL2) complex, leading to its degradation by the proteasome (By similarity). Ubiquitinated by TRIM35 via 'lys-48' and 'Lys-63'-linked ubiquitination leading to inhibition of NLRP3 inflammasome activation (By similarity).

The disulfide bond in the pyrin domain might play a role in reactive oxygen species-mediated activation.

Palmitoylation by ZDHHC12 inhibits the NLRP3 inflammasome by promoting NLRP3 degradation by the chaperone-mediated autophagy pathway. Following palmitoylation, HSPA8/HSC70 recognizes and binds the KFERQ-like motifs on NLRP3 and promotes NLRP3 recruitment to lysosomes, where it is degraded via the chaperone-mediated autophagy pathway in a LAMP2-dependent process. Palmitoylation by ZDHHC5 enhances its binding to NEK7 leading to inflammasome assembly and activation. Depalmitoylated by ABHD17A.

Degraded via selective autophagy following interaction with Irgm1. Irgm1 promotes NLRP3 recruitment to autophagosome membranes, promoting its SQSTM1/p62-dependent autophagy-dependent degradation.

Belongs to the NLRP family.

Expressed with high levels in peripheral blood leukocytes, including Th2 lymphocytes and macrophages (PubMed:15302403, PubMed:16546100, PubMed:26098997, PubMed:28847925). Expressed at low levels in resting osteoblasts (at protein level) (PubMed:17907925).

• Cytoplasm
• Cytosol
• Inflammasome
• Cytoplasm
• Cytoskeleton
• Microtubule organizing center
• Golgi apparatus membrane
• Endoplasmic reticulum
• Mitochondrion
• Secreted
• Nucleus
• In macrophages, under resting conditions, mainly located in the cytosol and on membranes of various organelles, such as endoplasmic reticulum, mitochondria and Golgi: forms an inactive double-ring cage that is primarily localized on membranes (PubMed:23502856, PubMed:28716882, PubMed:34861190). Upon activation, NLRP3 is transported to microtubule organizing center (MTOC), where it is unlocked by NEK7, leading to its relocalization to dispersed trans-Golgi network (dTGN) vesicle membranes for the formation of an active inflammasome complex (PubMed:34861190). Recruited to dTGN vesicle membranes by binding to phosphatidylinositol 4-phosphate (PtdIns4P) (PubMed:30487600). After the induction of pyroptosis, inflammasome specks are released into the extracellular space where they can further promote IL1B processing and where they can be engulfed by macrophages. Phagocytosis induces lysosomal damage and inflammasome activation in the recipient cells (PubMed:24952504, PubMed:24952505). In the Th2 subset of CD4(+) helper T-cells, mainly located in the nucleus (PubMed:26098997). Nuclear localization depends upon KPNA2 (PubMed:26098997). In the Th1 subset of CD4(+) helper T-cells, mainly cytoplasmic (PubMed:26098997).

Cias1, Mmig1, Nalp3, Pypaf1, Nlrp3, Cold autoinflammatory syndrome 1 protein homolog, Cryopyrin, Mast cell maturation-associated-inducible protein 1, PYRIN-containing APAF1-like protein 1

• entrezGene:216799
• swissprot:Q8R4B8

Proteins

Immunology & Infectious Disease

• Immuno-oncology
• Neuroscience

118275Da