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Nlrp3

Developmental stage

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

Domain

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.

Function

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). Involved in the homeostatic wound healing response to tissue injury, a multistep cascade that guides neutrophil migration to necrotic sites while avoiding collateral damage of healthy tissues. ATP released from necrotic cells triggers activation of NLRP3 inflammasome through P2RX7 signaling leading to neutrophil adhesion to the vascular endothelium close to the injury site (PubMed:20947763). 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).

Post-translational modifications

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) Phosphorylated by LATS1 and LATS2 at Ser-261 following palmitoylation by ZDHHC1, promoting its relocalization to the microtubule organizing center (MTOC), where NLRP3 is activated by NEK7, leading to inflammasome assembly and activation (By similarity).

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). Undergoes 'Lys-27'-linked polyubiquitination by MARCHF5, leading to NLRP3-NEK7 complex formation and NLRP3 oligomerization (By similarity).

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

Palmitoylation by ZDHHC12 promotes NLRP3 degradation by the chaperone-mediated autophagy pathway (CMA) and therefore limits NLRP3 inflammasome activation. Interaction with ZDHHC12, and hence NLRP3 palmitoylation, is enhanced by ABHD8 (By similarity). 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 (By similarity). Palmitoylation at Cys-834 and Cys-835 by ZDHHC5 enhances its binding to NEK7 leading to inflammasome assembly and activation (By similarity). Palmitoylation at Cys-126 and Cys-955 by ZDHHC1 facilitates phosphorylation at Ser-261 by LATS1 and LATS2, promoting its relocalization to the microtubule organizing center (MTOC), where NLRP3 is activated by NEK7, leading to inflammasome assembly and activation (PubMed:39173637). Depalmitoylated by ABHD17A (By similarity).

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

Sequence Similarities

Belongs to the NLRP family.

Tissue Specificity

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).

Cellular localization

Alternative names

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

swissprot:Q8R4B8 entrezGene:216799

Other research areas