Nlrp3
entrez
287362
canonical
uniprot
D4A523
canonical
ensembl
ENSRNOG00000003170
resolver
ensp
ENSRNOP00000004280
resolver
ensp
ENSRNOP00000072545
resolver
enst
ENSRNOT00000004280
resolver
enst
ENSRNOT00000086710
resolver
genesymbol
Nlrp3
resolver
uniprot
A0A0G2K391
resolver
uniprot_entry
A0A0G2K391_RAT
resolver
uniprot_entry
NLRP3_RAT
resolver
activity_regulation
ACTIVITY REGULATION: Under resting conditions, NLRP3 binds ADP and is autoinhibited (By similarity). Inactive NLRP3 forms homodecameric double-ring cages that hide pyrin domains within NACHT-LRR rings to avoid premature activation. 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. Almost all stimuli trigger intracellular K(+) efflux. These stimuli lead to membrane perturbations that induce activation of NLRP3. 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 recruitment of PYCARD/ASC for the formation of an active inflammasome complex. NEK7-activated NLRP3 forms a disk-shaped inflammasome. NLRP3 and PYCARD/ASC interact via their respective pyrin domains; interaction initiates speck formation (nucleation) which greatly enhances further addition of soluble PYCARD/ASC molecules to the speck in a prion-like polymerization process (By similarity). Clustered PYCARD/ASC nucleates the formation of CASP1 filaments through the interaction of their respective CARD domains, acting as a platform for CASP1 polymerization and activation. Active CASP1 then processes IL1B and IL18 precursors, leading to the release of mature cytokines in the extracellular milieu and inflammatory response (By similarity). NLRP3 inflammasome assembly is inhibited by IRGM, which impedes NLRP3 oligomerization (By similarity). NLRP3 inflammasome is activated by cyclic di-AMP (c-di-AMP) and cyclic di-GMP (c-di-GMP), which enhance polymerization (By similarity). NLRP3 inflammasome is inhibited by cyclic AMP (cAMP), which directly binds NLRP3; inhibition is relieved by calcium-sensing receptor CASR, which inhibits production of cAMP (By similarity). Specifically inhibited by sulfonylurea MCC950 (also named CP-456,773, CRID3), a potent and specific small-molecule inhibitor of the NLRP3 inflammasome that acts by preventing ATP hydrolysis (By similarity). {ECO:0000250|UniProtKB:Q8R4B8, ECO:0000250|UniProtKB:Q96P20}.
uniprot
proteins
amino_acid_sequence
MKMMSVRCKLAQYLEDLEDVDLKKFKMHLEDYPPEKGCVPIPRGQMEKADHLDLATLMIDFNGEEKAWGMAVWIFAAINRRDLWEKAKKDQPEWNDACTSNLSMVCQEDSLEEEWIGLLGYLSRISICKKKKDYCKIYRRHVRSRFYSIKDRNARLGESVDLNRRYTQLQLVKEHPSKQEREHELLTIGRTKMWDRPMSSLKLELLFEPEDEHLEPVHTVVFQGAAGIGKTILARKIMLDWALGKLFKDKFDYLFFIHCREVSLRAPKSLADLIISCWPDPNPPVCKILCKPSRILFLMDGFDELQGAFDEHIEEVCTDWQKAVRGDILLSSLIRKKLLPKASLLITTRPVALEKLQHLLDHPRHVEILGFSEAKRKEYFFKYFSNELQAREAFRLIQENEILFTMCFIPLVCWIVCTGLKQQMETGKSLAQTSKTTTAVYVFFLSSLLQSRGGIEEHLFSAYLPGLCSLAADGIWNQKILFEECDLRKHGLQKTDVSAFLRMNVFQKEVDCERFYSFSHMTFQEFFAAMYYLLEEEEEGVTVRKGPEGCSDLLNRDVKVLLENYGKFEKGYLIFVVRFLFGLVNQERTSYLEKKLSCKISQQVRLELLKWIEVKAKAKKLQRQPSQLELFYCLYEMQEEDFVQSAMGHFPKIEINLSTRMDHVVSSFCIKNCHRVKTLSLGFLHNSPKEEEEEKRGSQPLDQVQCVFPDPHVACSSRLVNCCLTSSFCRGLFSSLSTNQSLTELDLSDNTLGDPGMRVLCEALQHPGCNIQRLWLGRCGLTHQCCFNISSVLSSSQKLVELDLSDNALGDFGVRLLCVGLKHLLCNLQKLWLVSCCLTSACCQDLALVLSSNHSLTRLYIGENALGDSGVQVLCEKMKDPQCNLQKLGLVNSGLTSLCCSALTSVLKTNQNLTHLYLRSNALGDMGLKLLCEGLLHPDCKLQMLELDNCSLTSHSCWDLSTILTHNQSLRKLNLSNNDLGDLCVVTLCEVLKQQGCLLQSLQLGEMYLNCETKRTLEALQEEKPELTVVFEISW
uniprot
proteins
ec_number
3.6.4.-
uniprot
proteins
function
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. 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. 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. Activation of NLRP3 inflammasome is also required for HMGB1 secretion; stimulating inflammatory responses (By similarity). 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 (By similarity). 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. Almost all stimuli trigger intracellular K(+) efflux (By similarity). 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. Associates with dTGN vesicle membranes by binding to phosphatidylinositol 4-phosphate (PtdIns4P). Shows ATPase activity (By similarity). {ECO:0000250|UniProtKB:Q8R4B8, ECO:0000250|UniProtKB:Q96P20}.; FUNCTION: 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. During Th2 differentiation, required for optimal IRF4 binding to IL4 promoter and for IRF4-dependent IL4 transcription. Binds to the consensus DNA sequence 5'-GRRGGNRGAG-3'. May also participate in the transcription of IL5, IL13, GATA3, CCR3, CCR4 and MAF. {ECO:0000250|UniProtKB:Q8R4B8}.
uniprot
proteins
mass_dalton
118540
uniprot
proteins
post_translational_modification
PTM: Phosphorylation by MAPK8/JNK1 increases inflammasome activation by promoting deubiquitination by BRCC3 and NLRP3 homooligomerization. Phosphorylation at Ser-805 by CSNK1A1 prevents inflammasome activation by preventing NEK7 recruitment. Phosphorylation at Ser-5 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. Phosphorylation at Ser-293 by PKD/PRKD1 promotes NLRP3 inflammasome assembly (By similarity). Phosphorylation by ERK1/MAPK3 promotes NLRP3 inflammasome assembly (By similarity). Phosphorylation by BTK (at Tyr-134, Tyr-138 and Tyr-166) in the region that mediates binding to phosphatidylinositol phosphate, promotes relocalization of NLRP3 and assembly of the NLRP3 inflammasome. Phosphorylation at Tyr-860 inhibits NLRP3 inflammasome assembly: dephosphorylation by PTPN22 promotes inflammasome activation (By similarity). Phosphorylated by LATS1 and LATS2 at Ser-263 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). {ECO:0000250|UniProtKB:Q8R4B8, ECO:0000250|UniProtKB:Q96P20}.; PTM: Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. Ubiquitination does not lead to degradation, but inhibits inflammasome activation. Deubiquitination is catalyzed by BRCC3 and associated with NLRP3 activation and inflammasome assembly. 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. Ubiquitinated by TRIM31 via 'Lys-48'-linked ubiquitination, leading to its degradation by the proteasome (By similarity). Ubiquitinated at Lys-689 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). {ECO:0000250|UniProtKB:Q8R4B8, ECO:0000250|UniProtKB:Q96P20}.; PTM: The disulfide bond in the pyrin domain might play a role in reactive oxygen species-mediated activation. {ECO:0000250|UniProtKB:Q96P20}.; PTM: 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 greatly 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. Palmitoylation at Cys-836 and Cys-837 by ZDHHC5 enhances its binding to NEK7 leading to inflammasome assembly and activation. Palmitoylation at Cys-128 and Cys-957 by ZDHHC1 facilitates phosphorylation at Ser-263 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. Depalmitoylated by ABHD17A. {ECO:0000250|UniProtKB:Q96P20}.; PTM: Degraded via selective autophagy following interaction with IRGM. IRGM promotes NLRP3 recruitment to autophagosome membranes, promoting its SQSTM1/p62-dependent autophagy-dependent degradation. {ECO:0000250|UniProtKB:Q96P20}.
uniprot
proteins
protein_family
NLRP family
uniprot
proteins
pubmed
15057822
uniprot
proteins
sequence_length
1035
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000250|UniProtKB:Q8R4B8}. Inflammasome {ECO:0000250|UniProtKB:Q8R4B8}. Cytoplasm, cytoskeleton, microtubule organizing center {ECO:0000250|UniProtKB:Q8R4B8}. Golgi apparatus membrane {ECO:0000250|UniProtKB:Q8R4B8}. Endoplasmic reticulum {ECO:0000250|UniProtKB:Q8R4B8}. Mitochondrion {ECO:0000250|UniProtKB:Q8R4B8}. Secreted {ECO:0000250|UniProtKB:Q8R4B8}. Nucleus {ECO:0000250|UniProtKB:Q8R4B8}. Note=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. 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. Recruited to dTGN vesicle membranes by binding to phosphatidylinositol 4-phosphate (PtdIns4P). 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. In the Th2 subset of CD4(+) helper T cells, mainly located in the nucleus. Nuclear localization depends upon KPNA2. In the Th1 subset of CD4(+) helper T cells, mainly cytoplasmic. {ECO:0000250|UniProtKB:Q8R4B8}.
uniprot
proteins