Nlrp3
entrez
216799
canonical
uniprot
Q8R4B8
canonical
ensembl
ENSMUSG00000032691
resolver
ensp
ENSMUSP00000078440
resolver
ensp
ENSMUSP00000098707
resolver
genesymbol
Nlrp3
resolver
genesymbol_syn
Cias1
resolver
genesymbol_syn
Mmig1
resolver
genesymbol_syn
Nalp3
resolver
genesymbol_syn
Pypaf1
resolver
uniprot
Q1JQ87
resolver
uniprot
Q1JQ88
resolver
uniprot
Q6JEL0
resolver
uniprot
T1W2H6
resolver
uniprot_entry
NLRP3_MOUSE
resolver
uniprot_sec
Q1JQ87
resolver
uniprot_sec
Q1JQ88
resolver
uniprot_sec
Q6JEL0
resolver
uniprot_sec
T1W2H6
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 (PubMed:30518920, PubMed:34861190, PubMed:35254907). 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:16407889, PubMed:18403674, PubMed:19362020). Almost all stimuli trigger intracellular K(+) efflux (PubMed:23809161). These stimuli lead to membrane perturbations that induce activation of NLRP3 (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 and recruitment of PYCARD/ASC for the formation of an active inflammasome complex (PubMed:26642356, PubMed:26814970, PubMed:28716882, PubMed:30487600, PubMed:34615873, PubMed:34861190). NEK7-activated NLRP3 forms a disk-shaped inflammasome (By similarity). 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 (PubMed:24630723). 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 (By similarity). 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 (PubMed:40419769). 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 (PubMed:23143333). 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 (PubMed:35254907). {ECO:0000250|UniProtKB:Q96P20, ECO:0000269|PubMed:16407889, ECO:0000269|PubMed:18403674, ECO:0000269|PubMed:19362020, ECO:0000269|PubMed:23143333, ECO:0000269|PubMed:23809161, ECO:0000269|PubMed:24630723, ECO:0000269|PubMed:26642356, ECO:0000269|PubMed:26814970, ECO:0000269|PubMed:28716882, ECO:0000269|PubMed:30487600, ECO:0000269|PubMed:30518920, ECO:0000269|PubMed:34615873, ECO:0000269|PubMed:34861190, ECO:0000269|PubMed:35254907, ECO:0000269|PubMed:40419769}.
uniprot
proteins
amino_acid_sequence
MTSVRCKLAQYLEDLEDVDLKKFKMHLEDYPPEKGCIPVPRGQMEKADHLDLATLMIDFNGEEKAWAMAVWIFAAINRRDLWEKAKKDQPEWNDTCTSHSSMVCQEDSLEEEWMGLLGYLSRISICKKKKDYCKMYRRHVRSRFYSIKDRNARLGESVDLNSRYTQLQLVKEHPSKQEREHELLTIGRTKMRDSPMSSLKLELLFEPEDGHSEPVHTVVFQGAAGIGKTILARKIMLDWALGKLFKDKFDYLFFIHCREVSLRTPRSLADLIVSCWPDPNPPVCKILRKPSRILFLMDGFDELQGAFDEHIGEVCTDWQKAVRGDILLSSLIRKKLLPKASLLITTRPVALEKLQHLLDHPRHVEILGFSEAKRKEYFFKYFSNELQAREAFRLIQENEVLFTMCFIPLVCWIVCTGLKQQMETGKSLAQTSKTTTAVYVFFLSSLLQSRGGIEEHLFSDYLQGLCSLAADGIWNQKILFEECDLRKHGLQKTDVSAFLRMNVFQKEVDCERFYSFSHMTFQEFFAAMYYLLEEEAEGETVRKGPGGCSDLLNRDVKVLLENYGKFEKGYLIFVVRFLFGLVNQERTSYLEKKLSCKISQQVRLELLKWIEVKAKAKKLQWQPSQLELFYCLYEMQEEDFVQSAMDHFPKIEINLSTRMDHVVSSFCIKNCHRVKTLSLGFFHNSPKEEEEERRGGRPLDQVQCVFPDTHVACSSRLVNCCLTSSFCRGLFSSLSTNRSLTELDLSDNTLGDPGMRVLCEALQHPGCNIQRLWLGRCGLSHQCCFDISSVLSSSQKLVELDLSDNALGDFGIRLLCVGLKHLLCNLQKLWLVSCCLTSACCQDLALVLSSNHSLTRLYIGENALGDSGVQVLCEKMKDPQCNLQKLGLVNSGLTSICCSALTSVLKTNQNFTHLYLRSNALGDTGLRLLCEGLLHPDCKLQMLELDNCSLTSHSCWNLSTILTHNHSLRKLNLGNNDLGDLCVVTLCEVLKQQGCLLQSLQLGEMYLNRETKRALEALQEEKPELTIVFEISW
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 (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). {ECO:0000250|UniProtKB:Q96P20, ECO:0000269|PubMed:16407888, ECO:0000269|PubMed:16407889, ECO:0000269|PubMed:16407890, ECO:0000269|PubMed:16546100, ECO:0000269|PubMed:17008311, ECO:0000269|PubMed:18403674, ECO:0000269|PubMed:19362020, ECO:0000269|PubMed:20947763, ECO:0000269|PubMed:22801494, ECO:0000269|PubMed:23582325, ECO:0000269|PubMed:23809161, ECO:0000269|PubMed:26642356, ECO:0000269|PubMed:26814970, ECO:0000269|PubMed:27374331, ECO:0000269|PubMed:27929086, ECO:0000269|PubMed:28656979, ECO:0000269|PubMed:28847925, ECO:0000269|PubMed:30487600, ECO:0000269|PubMed:30518920, ECO:0000269|PubMed:34615873, ECO:0000269|PubMed:34861190, ECO:0000269|PubMed:37001519}.; 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 (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). {ECO:0000269|PubMed:26098997}.
uniprot
proteins
mass_dalton
118275
uniprot
proteins
mutagenesis
MUTAGEN 126; /note="C->A: Decreased activation of the NLRP3 inflammasome; when associated with A-955."; /evidence="ECO:0000269|PubMed:39173637"; MUTAGEN 127..143; /note="KKKKDYCKMYRRHVRSR->AAAADYCKMYAAHVASA: In linker-mutant; strongly reduced binding to phosphorylated phosphatidylinositides. Abolished ability to form homooligomeric double-ring cages that hide pyrin domains to avoid premature activation."; /evidence="ECO:0000269|PubMed:34861190"; MUTAGEN 127..130; /note="KKKK->AAAA: In 4KA mutant; abolished binding to phosphatidylinositol 4-phosphate (PtdIns4P) and recruitment to dispersed trans-Golgi network (dTGN) vesicle membranes."; /evidence="ECO:0000269|PubMed:30487600"; MUTAGEN 194; /note="S->A: Abolished phosphorylation by JNK1 leading to decreased activation of the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:28943315"; MUTAGEN 291; /note="S->A: Abolished phosphorylation by PKD/PRKD1, leading to prevent NLRP3 inflammasome activation."; /evidence="ECO:0000269|PubMed:28716882"; MUTAGEN 291; /note="S->E: Mimics phosphorylation state; despite this, does not promote activation of the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:28716882"; MUTAGEN 754; /note="G->A,R: Increases interaction with NEK7."; /evidence="ECO:0000269|PubMed:26642356"; MUTAGEN 771..776; /note="RLWLGR->ELTLGE: In LRRm3 mutant; abolished ability to form homooligomeric double-ring cages that hide pyrin domains to avoid premature activation."; /evidence="ECO:0000269|PubMed:34861190"; MUTAGEN 781..785; /note="HQCCF->ERCCA: In LRRm5 mutant; abolished ability to form homooligomeric double-ring cages that hide pyrin domains to avoid premature activation."; /evidence="ECO:0000269|PubMed:34861190"; MUTAGEN 803; /note="S->D: Mimics phosphorylation state; impaired ability to recruit NEK7, leding to decreased activation of the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:34615873"; MUTAGEN 809..813; /note="DFGIR->RAGIE: In LRRm4 mutant; abolished ability to form homooligomeric double-ring cages that hide pyrin domains to avoid premature activation."; /evidence="ECO:0000269|PubMed:34861190"; MUTAGEN 830; /note="W->A: In LRRm1 mutant; abolished ability to form homooligomeric double-ring cages that hide pyrin domains to avoid premature activation; when associated with C-858."; /evidence="ECO:0000269|PubMed:34861190"; MUTAGEN 858; /note="Y->C: In LRRm1 mutant; abolished ability to form homooligomeric double-ring cages that hide pyrin domains to avoid premature activation; when associated with A-830."; /evidence="ECO:0000269|PubMed:34861190"; MUTAGEN 955; /note="C->A: Decreased activation of the NLRP3 inflammasome; when associated with A-126."; /evidence="ECO:0000269|PubMed:39173637"; MUTAGEN 970; /note="K->E: In LRR6 mutant; does not affect ability to form homooligomeric double-ring cages that hide pyrin domains to avoid premature activation; when associated with R-1001 and A-1029."; /evidence="ECO:0000269|PubMed:34861190"; MUTAGEN 1001; /note="Q->R: In LRR6 mutant; does not affect ability to form homooligomeric double-ring cages that hide pyrin domains to avoid premature activation; when associated with E-970 and A-1029."; /evidence="ECO:0000269|PubMed:34861190"; MUTAGEN 1008..1013; /note="NRETKR->REERTKE: In LRRm2 mutant; abolished ability to form homooligomeric double-ring cages that hide pyrin domains to avoid premature activation."; /evidence="ECO:0000269|PubMed:34861190"; MUTAGEN 1029; /note="F->A: In LRR6 mutant; does not affect ability to form homooligomeric double-ring cages that hide pyrin domains to avoid premature activation; when associated with E-970 and R-1001."; /evidence="ECO:0000269|PubMed:34861190
uniprot
proteins
post_translational_modification
PTM: 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). {ECO:0000250|UniProtKB:Q96P20, ECO:0000269|PubMed:27043286, ECO:0000269|PubMed:28465465, ECO:0000269|PubMed:28716882, ECO:0000269|PubMed:28943315, ECO:0000269|PubMed:34554188, ECO:0000269|PubMed:34615873}.; PTM: 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). {ECO:0000250|UniProtKB:Q96P20, ECO:0000269|PubMed:22948162, ECO:0000269|PubMed:23246432, ECO:0000269|PubMed:27929086}.; 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 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). {ECO:0000250|UniProtKB:Q96P20, ECO:0000269|PubMed:39173637}.; PTM: Degraded via selective autophagy following interaction with Irgm1. Irgm1 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
14688236
uniprot
proteins
pubmed
15302403
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16407888
uniprot
proteins
pubmed
16407889
uniprot
proteins
pubmed
16407890
uniprot
proteins
pubmed
16546100
uniprot
proteins
pubmed
17008311
uniprot
proteins
pubmed
17907925
uniprot
proteins
pubmed
18403674
uniprot
proteins
pubmed
19362020
uniprot
proteins
pubmed
19468303
uniprot
proteins
pubmed
20802146
uniprot
proteins
pubmed
20947763
uniprot
proteins
pubmed
22801494
uniprot
proteins
pubmed
22948162
uniprot
proteins
pubmed
23143333
uniprot
proteins
pubmed
23246432
uniprot
proteins
pubmed
23502856
uniprot
proteins
pubmed
23582325
uniprot
proteins
pubmed
23809161
uniprot
proteins
pubmed
23809162
uniprot
proteins
pubmed
24630723
uniprot
proteins
pubmed
24952504
uniprot
proteins
pubmed
24952505
uniprot
proteins
pubmed
26098997
uniprot
proteins
pubmed
26553871
uniprot
proteins
pubmed
26642356
uniprot
proteins
pubmed
26814970
uniprot
proteins
pubmed
27043286
uniprot
proteins
pubmed
27374331
uniprot
proteins
pubmed
27929086
uniprot
proteins
pubmed
28465465
uniprot
proteins
pubmed
28656979
uniprot
proteins
pubmed
28716882
uniprot
proteins
pubmed
28847925
uniprot
proteins
pubmed
28943315
uniprot
proteins
pubmed
30487600
uniprot
proteins
pubmed
30518920
uniprot
proteins
pubmed
31511697
uniprot
proteins
pubmed
34341353
uniprot
proteins
pubmed
34554188
uniprot
proteins
pubmed
34615873
uniprot
proteins
pubmed
34861190
uniprot
proteins
pubmed
35254907
uniprot
proteins
pubmed
36178239
uniprot
proteins
pubmed
37001519
uniprot
proteins
pubmed
39173637
uniprot
proteins
pubmed
40419769
uniprot
proteins
sequence_length
1033
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:14688236, ECO:0000269|PubMed:23502856, ECO:0000269|PubMed:26098997, ECO:0000269|PubMed:36178239}. Inflammasome {ECO:0000269|PubMed:14688236, ECO:0000269|PubMed:23502856, ECO:0000269|PubMed:26098997}. Cytoplasm, cytoskeleton, microtubule organizing center {ECO:0000269|PubMed:28656979, ECO:0000269|PubMed:34861190}. Golgi apparatus membrane {ECO:0000269|PubMed:28716882, ECO:0000269|PubMed:30487600}. Endoplasmic reticulum {ECO:0000269|PubMed:23502856}. Mitochondrion {ECO:0000269|PubMed:23582325}. Secreted {ECO:0000269|PubMed:24952504}. Nucleus {ECO:0000269|PubMed:26098997}. 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 (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). {ECO:0000269|PubMed:23502856, ECO:0000269|PubMed:24952504, ECO:0000269|PubMed:24952505, ECO:0000269|PubMed:26098997, ECO:0000269|PubMed:28716882, ECO:0000269|PubMed:30487600, ECO:0000269|PubMed:34861190}.
uniprot
proteins