NLRP3
entrez
114548
canonical
uniprot
Q96P20
canonical
ensembl
ENSG00000162711
resolver
ensp
ENSP00000294752
resolver
ensp
ENSP00000337383
resolver
ensp
ENSP00000355452
resolver
ensp
ENSP00000375703
resolver
ensp
ENSP00000375704
resolver
ensp
ENSP00000513275
resolver
ensp
ENSP00000520480
resolver
ensp
ENSP00000568508
resolver
ensp
ENSP00000568509
resolver
ensp
ENSP00000629564
resolver
enst
ENST00000336119
resolver
enst
ENST00000348069
resolver
enst
ENST00000366496
resolver
enst
ENST00000391827
resolver
enst
ENST00000391828
resolver
enst
ENST00000697350
resolver
enst
ENST00000697408
resolver
enst
ENST00000898449
resolver
enst
ENST00000898450
resolver
genesymbol
NLRP3
resolver
genesymbol_syn
C1orf7
resolver
genesymbol_syn
CIAS1
resolver
genesymbol_syn
NALP3
resolver
genesymbol_syn
PYPAF1
resolver
hgnc
HGNC:16400
resolver
uniprot
A0A024R5Q0
resolver
uniprot
A0A7I2PJH0
resolver
uniprot
A0A7I2PMC6
resolver
uniprot
A0A7I2PRX0
resolver
uniprot
A0A7I2R3P8
resolver
uniprot
B2RC97
resolver
uniprot
B7ZKS9
resolver
uniprot
B7ZKT2
resolver
uniprot
B7ZKT3
resolver
uniprot
O75434
resolver
uniprot
Q17RS2
resolver
uniprot
Q59H68
resolver
uniprot
Q5JQS8
resolver
uniprot
Q5JQS9
resolver
uniprot
Q6TG35
resolver
uniprot
Q8TCW0
resolver
uniprot
Q8TEU9
resolver
uniprot
Q8WXH9
resolver
uniprot_entry
A0A7I2PJH0_HUMAN
resolver
uniprot_entry
A0A7I2PMC6_HUMAN
resolver
uniprot_entry
A0A7I2PRX0_HUMAN
resolver
uniprot_entry
A0A7I2R3P8_HUMAN
resolver
uniprot_entry
NLRP3_HUMAN
resolver
uniprot_sec
A0A024R5Q0
resolver
uniprot_sec
B2RC97
resolver
uniprot_sec
B7ZKS9
resolver
uniprot_sec
B7ZKT2
resolver
uniprot_sec
B7ZKT3
resolver
uniprot_sec
O75434
resolver
uniprot_sec
Q17RS2
resolver
uniprot_sec
Q59H68
resolver
uniprot_sec
Q5JQS8
resolver
uniprot_sec
Q5JQS9
resolver
uniprot_sec
Q6TG35
resolver
uniprot_sec
Q8TCW0
resolver
uniprot_sec
Q8TEU9
resolver
uniprot_sec
Q8WXH9
resolver
activity_regulation
ACTIVITY REGULATION: Under resting conditions, NLRP3 binds ADP and is autoinhibited (PubMed:35114687). Inactive NLRP3 forms homodecameric double-ring cages that hide pyrin domains within NACHT-LRR rings to avoid premature activation (PubMed:35114687). 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:18604214, PubMed:19414800, PubMed:35114687). Activated upon human coronavirus SARS-CoV-2 infection (PubMed:33231615, PubMed:34133077). Almost all stimuli trigger intracellular K(+) efflux (By similarity). These stimuli lead to membrane perturbations that induce 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 recruitment of PYCARD/ASC for the formation of an active inflammasome complex (PubMed:30487600, PubMed:30612879, PubMed:36442502, PubMed:39173637). NEK7-activated NLRP3 forms a disk-shaped inflammasome (PubMed:36442502). 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:24630722, PubMed:27432880, PubMed:28465465, PubMed:35559676, PubMed:36142182, PubMed:36442502). 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 (PubMed:24630722). Active CASP1 then processes IL1B and IL18 precursors, leading to the release of mature cytokines in the extracellular milieu and inflammatory response (PubMed:24630722). NLRP3 inflammasome assembly is inhibited by IRGM, which impedes NLRP3 oligomerization (PubMed:30612879). NLRP3 inflammasome is activated by cyclic di-AMP (c-di-AMP) and cyclic di-GMP (c-di-GMP), which enhance polymerization (PubMed:24008845). 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:32843625). 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:25686105, PubMed:31086327, PubMed:31086329, PubMed:34687713, PubMed:35114687, PubMed:35254907). {ECO:0000250|UniProtKB:Q8R4B8, ECO:0000269|PubMed:16407889, ECO:0000269|PubMed:18403674, ECO:0000269|PubMed:18604214, ECO:0000269|PubMed:19414800, ECO:0000269|PubMed:24008845, ECO:0000269|PubMed:24630722, ECO:0000269|PubMed:25686105, ECO:0000269|PubMed:27432880, ECO:0000269|PubMed:28465465, ECO:0000269|PubMed:30487600, ECO:0000269|PubMed:30612879, ECO:0000269|PubMed:31086327, ECO:0000269|PubMed:31086329, ECO:0000269|PubMed:32843625, ECO:0000269|PubMed:33231615, ECO:0000269|PubMed:34133077, ECO:0000269|PubMed:34687713, ECO:0000269|PubMed:35114687, ECO:0000269|PubMed:35254907, ECO:0000269|PubMed:35559676, ECO:0000269|PubMed:36142182, ECO:0000269|PubMed:36442502, ECO:0000269|PubMed:39173637}.
uniprot
proteins
amino_acid_sequence
MKMASTRCKLARYLEDLEDVDLKKFKMHLEDYPPQKGCIPLPRGQTEKADHVDLATLMIDFNGEEKAWAMAVWIFAAINRRDLYEKAKRDEPKWGSDNARVSNPTVICQEDSIEEEWMGLLEYLSRISICKMKKDYRKKYRKYVRSRFQCIEDRNARLGESVSLNKRYTRLRLIKEHRSQQEREQELLAIGKTKTCESPVSPIKMELLFDPDDEHSEPVHTVVFQGAAGIGKTILARKMMLDWASGTLYQDRFDYLFYIHCREVSLVTQRSLGDLIMSCCPDPNPPIHKIVRKPSRILFLMDGFDELQGAFDEHIGPLCTDWQKAERGDILLSSLIRKKLLPEASLLITTRPVALEKLQHLLDHPRHVEILGFSEAKRKEYFFKYFSDEAQARAAFSLIQENEVLFTMCFIPLVCWIVCTGLKQQMESGKSLAQTSKTTTAVYVFFLSSLLQPRGGSQEHGLCAHLWGLCSLAADGIWNQKILFEESDLRNHGLQKADVSAFLRMNLFQKEVDCEKFYSFIHMTFQEFFAAMYYLLEEEKEGRTNVPGSRLKLPSRDVTVLLENYGKFEKGYLIFVVRFLFGLVNQERTSYLEKKLSCKISQQIRLELLKWIEVKAKAKKLQIQPSQLELFYCLYEMQEEDFVQRAMDYFPKIEINLSTRMDHMVSSFCIENCHRVESLSLGFLHNMPKEEEEEEKEGRHLDMVQCVLPSSSHAACSHGLVNSHLTSSFCRGLFSVLSTSQSLTELDLSDNSLGDPGMRVLCETLQHPGCNIRRLWLGRCGLSHECCFDISLVLSSNQKLVELDLSDNALGDFGIRLLCVGLKHLLCNLKKLWLVSCCLTSACCQDLASVLSTSHSLTRLYVGENALGDSGVAILCEKAKNPQCNLQKLGLVNSGLTSVCCSALSSVLSTNQNLTHLYLRGNTLGDKGIKLLCEGLLHPDCKLQVLELDNCNLTSHCCWDLSTLLTSSQSLRKLSLGNNDLGDLGVMMFCEVLKQQSCLLQNLGLSEMYFNYETKSALETLQEEKPELTVVFEPSW
uniprot
proteins
disease_involvement
DISEASE: Familial cold autoinflammatory syndrome 1 (FCAS1) [MIM:120100]: A rare autosomal dominant systemic inflammatory disease characterized by recurrent episodes of maculopapular rash associated with arthralgias, myalgias, fever and chills, swelling of the extremities, and conjunctivitis after generalized exposure to cold. Rarely, some patients may also develop late-onset renal amyloidosis. {ECO:0000269|PubMed:11687797, ECO:0000269|PubMed:11992256, ECO:0000269|PubMed:12355493, ECO:0000269|PubMed:12522564, ECO:0000269|PubMed:15593220, ECO:0000269|PubMed:17284928, ECO:0000269|PubMed:24952504}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Muckle-Wells syndrome (MWS) [MIM:191900]: A hereditary periodic fever syndrome characterized by fever, chronic recurrent urticaria, arthralgias, progressive sensorineural deafness, and reactive renal amyloidosis. The disease may be severe if generalized reactive amyloidosis occurs. {ECO:0000269|PubMed:11687797, ECO:0000269|PubMed:11992256, ECO:0000269|PubMed:12355493, ECO:0000269|PubMed:15593220, ECO:0000269|PubMed:24952504}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Chronic infantile neurologic cutaneous and articular syndrome (CINCA) [MIM:607115]: Rare congenital inflammatory disorder characterized by a triad of neonatal onset of cutaneous symptoms, chronic meningitis, and joint manifestations with recurrent fever and inflammation. {ECO:0000269|PubMed:12032915, ECO:0000269|PubMed:12483741, ECO:0000269|PubMed:14630794, ECO:0000269|PubMed:15231984, ECO:0000269|PubMed:15334500, ECO:0000269|PubMed:15593220, ECO:0000269|PubMed:24952504, ECO:0000269|PubMed:31086329}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Keratoendothelitis fugax hereditaria (KEFH) [MIM:148200]: An autosomal dominant corneal disease that periodically, and fleetingly, affects the corneal endothelium, stroma, and vision, eventually leading to central corneal stromal opacities in some patients. The disease is characterized by unilateral attacks of ocular pain, pericorneal injection, and photophobia. The acute symptoms vanish in 1-2 days but vision remains blurry for several weeks. The attacks start at the age of 3-12 years and can affect either eye. They generally decrease in frequency and get milder with age. {ECO:0000269|PubMed:29366613, ECO:0000269|PubMed:35559676}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Deafness, autosomal dominant, 34, with or without inflammation (DFNA34) [MIM:617772]: A form of sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNA34 is a postlingual, slowly progressive form with variable severity and variable additional features. Some DFNA34 patients have autoinflammatory manifestations. {ECO:0000269|PubMed:28847925}. Note=The disease may be caused by variants affecting the gene represented in this entry.
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:16407889, PubMed:18403674, PubMed:18604214, PubMed:23582325, PubMed:25686105, PubMed:27929086, PubMed:28656979, PubMed:28847925, PubMed:30487600, PubMed:30612879, PubMed:31086327, PubMed:31086329, PubMed:31189953, PubMed:33231615, PubMed:34133077, PubMed:34341353, PubMed:34512673, PubMed:36442502, PubMed:40250624, PubMed:40450990). 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:27432880, PubMed:28847925, PubMed:31189953, PubMed:33231615, PubMed:34133077, PubMed:34341353, PubMed:36142182, PubMed:36442502). 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:23582325, PubMed:28847925, PubMed:31189953, PubMed:33231615, PubMed:34133077, PubMed:34341353). 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 (By similarity). Under resting conditions, ADP-bound NLRP3 is autoinhibited (PubMed:35114687). 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:18604214, PubMed:19414800, PubMed:23871209). 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 (PubMed:36442502, PubMed:39173637). Associates with dTGN vesicle membranes by binding to phosphatidylinositol 4-phosphate (PtdIns4P) (PubMed:30487600, PubMed:34554188). Shows ATPase activity (PubMed:17483456). {ECO:0000250|UniProtKB:Q8R4B8, ECO:0000269|PubMed:16407889, ECO:0000269|PubMed:17483456, ECO:0000269|PubMed:18403674, ECO:0000269|PubMed:18604214, ECO:0000269|PubMed:19414800, ECO:0000269|PubMed:22801494, ECO:0000269|PubMed:23582325, ECO:0000269|PubMed:23871209, ECO:0000269|PubMed:25686105, ECO:0000269|PubMed:27432880, ECO:0000269|PubMed:27929086, ECO:0000269|PubMed:28656979, ECO:0000269|PubMed:28847925, ECO:0000269|PubMed:30487600, ECO:0000269|PubMed:30612879, ECO:0000269|PubMed:31086327, ECO:0000269|PubMed:31086329, ECO:0000269|PubMed:31189953, ECO:0000269|PubMed:33231615, ECO:0000269|PubMed:34133077, ECO:0000269|PubMed:34341353, ECO:0000269|PubMed:34554188, ECO:0000269|PubMed:35114687, ECO:0000269|PubMed:36142182, ECO:0000269|PubMed:36442502, ECO:0000269|PubMed:39173637, ECO:0000269|PubMed:40250624, ECO:0000269|PubMed:40450990}.; 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 (By similarity). During Th2 differentiation, required for optimal IRF4 binding to IL4 promoter and for IRF4-dependent IL4 transcription (By similarity). Binds to the consensus DNA sequence 5'-GRRGGNRGAG-3' (By similarity). May also participate in the transcription of IL5, IL13, GATA3, CCR3, CCR4 and MAF (By similarity). {ECO:0000250|UniProtKB:Q8R4B8}.
uniprot
proteins
mass_dalton
118173
uniprot
proteins
mutagenesis
MUTAGEN 2..7; /note="Missing: Strongly decreased interaction with MAVS and localization to mitochondria."; /evidence="ECO:0000269|PubMed:23582325"; MUTAGEN 5; /note="S->A: Decreased phosphorylation; increased activation of the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:28465465"; MUTAGEN 5; /note="S->D,E: Mimics phosphorylation state; decreased activation of the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:28465465"; MUTAGEN 7..12; /note="RCKLAR->ACALAA: Abolished formation of the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:28465465"; MUTAGEN 7; /note="R->E: Impaired ability to homooligomerize into ordered polymers."; /evidence="ECO:0000269|PubMed:35559676"; MUTAGEN 15; /note="E->R: Impaired ability to homooligomerize into ordered polymers. Complete loss of PYCARD/ASC filament nucleation."; /evidence="ECO:0000269|PubMed:24630722, ECO:0000269|PubMed:35559676"; MUTAGEN 22..23; /note="LK->PA: Loss of PYCARD/ASC-binding. No effect on GBP5-binding."; /evidence="ECO:0000269|PubMed:22461501"; MUTAGEN 23..24; /note="KK->EE: Impaired ability to homooligomerize into ordered polymers. Complete loss of PYCARD/ASC filament nucleation."; /evidence="ECO:0000269|PubMed:35559676"; MUTAGEN 23; /note="K->E: Complete loss of PYCARD/ASC filament nucleation; when associated with E-24."; /evidence="ECO:0000269|PubMed:24630722"; MUTAGEN 24; /note="K->E: Complete loss of PYCARD/ASC filament nucleation; when associated with E-23."; /evidence="ECO:0000269|PubMed:24630722"; MUTAGEN 27; /note="M->E: Impaired ability to homooligomerize into ordered polymers. Complete loss of PYCARD/ASC filament nucleation."; /evidence="ECO:0000269|PubMed:24630722, ECO:0000269|PubMed:35559676"; MUTAGEN 31; /note="D->V: Impaired ability to homooligomerize into ordered polymers. Decreased PYCARD/ASC filament nucleation."; /evidence="ECO:0000269|PubMed:35559676"; MUTAGEN 43; /note="R->E: Impaired ability to homooligomerize into ordered polymers."; /evidence="ECO:0000269|PubMed:35559676"; MUTAGEN 43; /note="R->W: Complete loss of PYCARD/ASC filament nucleation. Decreased PYCARD/ASC filament nucleation."; /evidence="ECO:0000269|PubMed:24630722"; MUTAGEN 51; /note="H->R: Does not affect ability to homooligomerize into ordered polymers."; /evidence="ECO:0000269|PubMed:35559676"; MUTAGEN 52; /note="V->G: Decreased interaction with MAPK4."; /evidence="ECO:0000269|PubMed:28656979"; MUTAGEN 64; /note="E->R: Complete loss of PYCARD/ASC filament nucleation."; /evidence="ECO:0000269|PubMed:24630722"; MUTAGEN 68; /note="W->A: Does not affect ubiquitination by the SCF(FBXL2) complex."; /evidence="ECO:0000269|PubMed:26037928"; MUTAGEN 73; /note="W->A: Decreased ubiquitination by the SCF(FBXL2) complex."; /evidence="ECO:0000269|PubMed:26037928"; MUTAGEN 77; /note="A->V: Induces the formation of short but ordered homopolymers."; /evidence="ECO:0000269|PubMed:35559676"; MUTAGEN 80; /note="R->E: Impaired ability to homooligomerize into ordered polymers. Decreased PYCARD/ASC filament nucleation."; /evidence="ECO:0000269|PubMed:35559676"; MUTAGEN 81; /note="R->E: Impaired ability to homooligomerize into ordered polymers. Decreased PYCARD/ASC filament nucleation."; /evidence="ECO:0000269|PubMed:35559676"; MUTAGEN 82; /note="D->R: Complete loss of PYCARD/ASC filament nucleation."; /evidence="ECO:0000269|PubMed:24630722"; MUTAGEN 130; /note="C->A: Decreased palmitoylation and activation of the NLRP3 inflammasome; when associated with A-958."; /evidence="ECO:0000269|PubMed:39173637"; MUTAGEN 136..143; /note="YRKKYRKY->FRKKFRKF: Decreased phosphorylation by BTK; when associated with F-168."; /evidence="ECO:0000269|PubMed:34554188"; MUTAGEN 143; /note="Y->R: Decreased ability to activate the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:36142182"; MUTAGEN 147; /note="R->E: Impaired ability to activate the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:36442502"; MUTAGEN 152; /note="E->R: Impaired ability to activate the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:36442502"; MUTAGEN 155; /note="N->A: Impaired ability to activate the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:36442502"; MUTAGEN 157; /note="R->E: Impaired ability to activate the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:36442502"; MUTAGEN 166; /note="K->E: Impaired ability to activate the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:36442502"; MUTAGEN 168; /note="Y->F: Decreased phosphorylation by BTK; when associated with 136-F--F-143."; /evidence="ECO:0000269|PubMed:34554188"; MUTAGEN 176; /note="E->R: Impaired ability to activate the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:36442502"; MUTAGEN 198; /note="S->A: Abolished phosphorylation by MAPK8/JNK1; decreased activation of the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:27929086"; MUTAGEN 198; /note="S->D,E: Mimicks phosphorylation state; increased activation of the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:27929086"; MUTAGEN 213; /note="D->R: Does not affect ability to activate the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:36442502"; MUTAGEN 228; /note="A->Q: Abolished binding to small-inhibitor MCC950 and ability to activate the NLRP3 inflammasome following stimulation with nigericin."; /evidence="ECO:0000269|PubMed:35114687"; MUTAGEN 231..233; /note="GKT->AAA: In Walker A mutant; abolished ATPase activity. Reduced ATP-binding leading to decreased activation of the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:17483456, ECO:0000269|PubMed:31086327"; MUTAGEN 265; /note="S->A: Abolished phosphorylation by LATS1, leading to decreased activation of the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:39173637"; MUTAGEN 302..306; /note="DGFDE->AGFAA,AGFNA: In Walker B mutant; abolished ATPase activity. Abolished binding to small-inhibitor MCC950."; /evidence="ECO:0000269|PubMed:31086327, ECO:0000269|PubMed:31086329"; MUTAGEN 324; /note="K->R: Complete loss of PYCARD/ASC filament nucleation."; /evidence="ECO:0000269|PubMed:37575012"; MUTAGEN 351; /note="R->T: Abolished binding to small-inhibitor MCC950 and ability to activate the NLRP3 inflammasome following stimulation with nigericin."; /evidence="ECO:0000269|PubMed:35114687"; MUTAGEN 359; /note="Q->A,R: Does not affect ability to activate the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:31189953, ECO:0000269|PubMed:36442502"; MUTAGEN 359; /note="Q->A: Decreased interaction with HSPA8/HSC70 and NLRP3 degradation by the chaperone-mediated autophagy pathway."; /evidence="ECO:0000269|PubMed:36586411"; MUTAGEN 364; /note="H->E: Does not affect ability to activate the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:36442502"; MUTAGEN 424; /note="Q->A: Impaired ability to activate the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:36442502"; MUTAGEN 430; /note="K->R: Complete loss of PYCARD/ASC filament nucleation."; /evidence="ECO:0000269|PubMed:37575012"; MUTAGEN 509; /note="Q->A: Impaired ability to activate the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:36442502"; MUTAGEN 578; /note="R->A: Abolished binding to small-inhibitor MCC950 and ability to activate the NLRP3 inflammasome following stimulation with nigericin."; /evidence="ECO:0000269|PubMed:35114687"; MUTAGEN 603; /note="Q->A: Decreased interaction with HSPA8/HSC70 and NLRP3 degradation by the chaperone-mediated autophagy pathway."; /evidence="ECO:0000269|PubMed:36586411"; MUTAGEN 619..621; /note="KKL->EEA: Does not affect autoinhibition of the protein."; /evidence="ECO:0000269|PubMed:35114687"; MUTAGEN 638..640; /note="QEE->RRR: Strongly decreased ability to activate the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:31189953"; MUTAGEN 689..698; /note="Missing: Loss of autoinhibition of the protein."; /evidence="ECO:0000269|PubMed:35114687"; MUTAGEN 689; /note="K->R: Abolished ubiquitination by the SCF(FBXL2) complex."; /evidence="ECO:0000269|PubMed:26037928"; MUTAGEN 707; /note="V->R: Decreased ability to activate the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:31189953"; MUTAGEN 735; /note="S->A: Does not affect activation of the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:34615873"; MUTAGEN 745; /note="E->R: Abolished ability to activate the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:31189953"; MUTAGEN 750; /note="D->R: Abolished ability to activate the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:31189953"; MUTAGEN 788..789; /note="FD->AR: Slightly impaired autoinhibition of the protein; when associated with A-831."; /evidence="ECO:0000269|PubMed:35114687"; MUTAGEN 788; /note="F->E: Slightly decreased ability to activate the NLRP3 inflammasome; when associated with E-813."; /evidence="ECO:0000269|PubMed:36142182"; MUTAGEN 789; /note="D->R: Slightly decreased ability to activate the NLRP3 inflammasome; when associated with D-816."; /evidence="ECO:0000269|PubMed:36142182"; MUTAGEN 798; /note="Q->A: Decreased interaction with HSPA8/HSC70 and NLRP3 degradation by the chaperone-mediated autophagy pathway."; /evidence="ECO:0000269|PubMed:36586411"; MUTAGEN 802; /note="E->R: Abolished ability to activate the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:31189953"; MUTAGEN 806; /note="S->A: Abolished phosphorylation by CSNK1A1; increased activation of the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:34615873"; MUTAGEN 806; /note="S->D,E: Mimics phosphorylation state; decreased activation of the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:34615873"; MUTAGEN 813; /note="F->E: Slightly decreased ability to activate the NLRP3 inflammasome; when associated with E-788."; /evidence="ECO:0000269|PubMed:36142182"; MUTAGEN 816; /note="R->D: Slightly decreased ability to activate the NLRP3 inflammasome; when associated with R-789."; /evidence="ECO:0000269|PubMed:36142182"; MUTAGEN 831; /note="K->A: Slightly impaired autoinhibition of the protein; when associated with 788-A-R-789."; /evidence="ECO:0000269|PubMed:35114687"; MUTAGEN 833; /note="W->G: Does not affect ability to activate the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:31189953"; MUTAGEN 837..838; /note="CC->SS: Abolished palmitoylation by ZDHHC5; when associated with S-838."; /evidence="ECO:0000269|PubMed:38092000"; MUTAGEN 844; /note="C->A: Abolished palmitoylation by ZDHHC12, preventing degradation by the chaperone-mediated autophagy pathway."; /evidence="ECO:0000269|PubMed:36586411"; MUTAGEN 861; /note="Y->F: Abolished phosphorylation."; /evidence="ECO:0000269|PubMed:27043286"; MUTAGEN 864; /note="E->R: Decreased ability to activate the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:31189953"; MUTAGEN 918; /note="Y->G: Decreased ability to activate the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:31189953"; MUTAGEN 958; /note="C->A: Decreased palmitoylation and activation of the NLRP3 inflammasome; when associated with A-130."; /evidence="ECO:0000269|PubMed:39173637"; MUTAGEN 995; /note="Q->A: Decreased interaction with HSPA8/HSC70 and NLRP3 degradation by the chaperone-mediated autophagy pathway."; /evidence="ECO:0000269|PubMed:36586411"; MUTAGEN 1035; /note="S->A: Does not affect activation of the NLRP3 inflammasome."; /evidence="ECO:0000269|PubMed:34615873
uniprot
proteins
post_translational_modification
PTM: Phosphorylation at Ser-198 by MAPK8/JNK1 increases inflammasome activation by promoting deubiquitination by BRCC3 and NLRP3 homooligomerization (PubMed:28943315). Phosphorylation at Ser-806 by CSNK1A1 prevents inflammasome activation by preventing NEK7 recruitment (PubMed:34615873). 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 (PubMed:28465465). Phosphorylation at Ser-295 by PKD/PRKD1 promotes NLRP3 inflammasome assembly (By similarity). Phosphorylation by ERK1/MAPK3 promotes NLRP3 inflammasome assembly (PubMed:24623131). Phosphorylation by BTK (at Tyr-136, Tyr-140, Tyr-143 and Tyr-168) in the region that mediates binding to phosphatidylinositol phosphate, promotes relocalization of NLRP3 and assembly of the NLRP3 inflammasome (PubMed:34554188). Phosphorylation at Tyr-861 inhibits NLRP3 inflammasome assembly: dephosphorylation by PTPN22 promotes inflammasome activation (PubMed:27043286). Phosphorylated by LATS1 and LATS2 at Ser-265 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 (PubMed:39173637). {ECO:0000250|UniProtKB:Q8R4B8, ECO:0000269|PubMed:24623131, ECO:0000269|PubMed:27043286, ECO:0000269|PubMed:28465465, ECO:0000269|PubMed:28943315, ECO:0000269|PubMed:34554188, ECO:0000269|PubMed:34615873, ECO:0000269|PubMed:39173637}.; PTM: Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination (PubMed:22948162, PubMed:27929086). Ubiquitination does not lead to degradation, but inhibits inflammasome activation (By similarity). Deubiquitination is catalyzed by BRCC3 and associated with NLRP3 activation and inflammasome assembly (By similarity). 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 (By similarity). Ubiquitinated by TRIM31 via 'Lys-48'-linked ubiquitination, leading to its degradation by the proteasome (PubMed:27929086). Ubiquitinated at Lys-689 by the SCF(FBXL2) complex, leading to its degradation by the proteasome (PubMed:26037928). Ubiquitinated by TRIM35 via 'lys-48' and 'Lys-63'-linked ubiquitination leading to inhibition of NLRP3 inflammasome activation (PubMed:34512673). Undergoes 'Lys-27'-linked polyubiquitination by MARCHF5, leading to NLRP3-NEK7 complex formation and NLRP3 oligomerization (PubMed:37575012). {ECO:0000250|UniProtKB:Q8R4B8, ECO:0000269|PubMed:22948162, ECO:0000269|PubMed:26037928, ECO:0000269|PubMed:27929086, ECO:0000269|PubMed:34512673, ECO:0000269|PubMed:37575012}.; PTM: Palmitoylation by ZDHHC12 promotes NLRP3 degradation by the chaperone-mediated autophagy pathway (CMA) and therefore limits NLRP3 inflammasome activation (PubMed:36586411, PubMed:39225180). 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 (PubMed:36586411). Palmitoylation at Cys-837 and Cys-838 by ZDHHC5 enhances its binding to NEK7 leading to inflammasome assembly and activation (PubMed:38092000). Palmitoylation at Cys-130 and Cys-958 by ZDHHC1 facilitates phosphorylation at Ser-265 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 (PubMed:38092000). {ECO:0000269|PubMed:36586411, ECO:0000269|PubMed:38092000, ECO:0000269|PubMed:39173637, ECO:0000269|PubMed:39225180}.; PTM: Degraded via selective autophagy following interaction with IRGM (PubMed:30612879). IRGM promotes NLRP3 recruitment to autophagosome membranes, promoting its SQSTM1/p62-dependent autophagy-dependent degradation (PubMed:30612879). {ECO:0000269|PubMed:30612879}.; PTM: The disulfide bond in the pyrin domain might play a role in reactive oxygen species-mediated activation. {ECO:0000305|PubMed:21880711}.; PTM: (Microbial infection) ADP-ribosylated by M.pneumoniae CARDS toxin in vitro. {ECO:0000269|PubMed:25538194}.
uniprot
proteins
protein_family
NLRP family
uniprot
proteins
pubmed
11042152
uniprot
proteins
pubmed
11687797
uniprot
proteins
pubmed
11786556
uniprot
proteins
pubmed
11992256
uniprot
proteins
pubmed
12032915
uniprot
proteins
pubmed
12355493
uniprot
proteins
pubmed
12483741
uniprot
proteins
pubmed
12522564
uniprot
proteins
pubmed
14630794
uniprot
proteins
pubmed
14662828
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15030775
uniprot
proteins
pubmed
15231984
uniprot
proteins
pubmed
15334500
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15593220
uniprot
proteins
pubmed
16407889
uniprot
proteins
pubmed
16710414
uniprot
proteins
pubmed
17164409
uniprot
proteins
pubmed
17284928
uniprot
proteins
pubmed
17431422
uniprot
proteins
pubmed
17483456
uniprot
proteins
pubmed
17907925
uniprot
proteins
pubmed
18403674
uniprot
proteins
pubmed
18604214
uniprot
proteins
pubmed
19414800
uniprot
proteins
pubmed
21124315
uniprot
proteins
pubmed
21880711
uniprot
proteins
pubmed
22461501
uniprot
proteins
pubmed
22801494
uniprot
proteins
pubmed
22948162
uniprot
proteins
pubmed
23229815
uniprot
proteins
pubmed
23305783
uniprot
proteins
pubmed
23430110
uniprot
proteins
pubmed
23582325
uniprot
proteins
pubmed
23809162
uniprot
proteins
pubmed
23871209
uniprot
proteins
pubmed
23955712
uniprot
proteins
pubmed
24008845
uniprot
proteins
pubmed
24517500
uniprot
proteins
pubmed
24531343
uniprot
proteins
pubmed
24623131
uniprot
proteins
pubmed
24630722
uniprot
proteins
pubmed
24952504
uniprot
proteins
pubmed
25354325
uniprot
proteins
pubmed
25538194
uniprot
proteins
pubmed
25686105
uniprot
proteins
pubmed
26037928
uniprot
proteins
pubmed
26347139
uniprot
proteins
pubmed
27043286
uniprot
proteins
pubmed
27432880
uniprot
proteins
pubmed
27929086
uniprot
proteins
pubmed
28465465
uniprot
proteins
pubmed
28656979
uniprot
proteins
pubmed
28847925
uniprot
proteins
pubmed
28943315
uniprot
proteins
pubmed
29366613
uniprot
proteins
pubmed
30487600
uniprot
proteins
pubmed
30612879
uniprot
proteins
pubmed
31086327
uniprot
proteins
pubmed
31086329
uniprot
proteins
pubmed
31189953
uniprot
proteins
pubmed
32843625
uniprot
proteins
pubmed
33231615
uniprot
proteins
pubmed
34133077
uniprot
proteins
pubmed
34341353
uniprot
proteins
pubmed
34512673
uniprot
proteins
pubmed
34524838
uniprot
proteins
pubmed
34554188
uniprot
proteins
pubmed
34615873
uniprot
proteins
pubmed
34687713
uniprot
proteins
pubmed
35114687
uniprot
proteins
pubmed
35254907
uniprot
proteins
pubmed
35559676
uniprot
proteins
pubmed
36142182
uniprot
proteins
pubmed
36442502
uniprot
proteins
pubmed
36586411
uniprot
proteins
pubmed
37575012
uniprot
proteins
pubmed
38092000
uniprot
proteins
pubmed
39173637
uniprot
proteins
pubmed
39225180
uniprot
proteins
pubmed
39333773
uniprot
proteins
pubmed
40250624
uniprot
proteins
pubmed
40450990
uniprot
proteins
sequence_length
1036
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:11786556, ECO:0000269|PubMed:14662828, ECO:0000269|PubMed:17164409, ECO:0000269|PubMed:38092000}. Inflammasome {ECO:0000269|PubMed:11786556, ECO:0000269|PubMed:14662828, ECO:0000269|PubMed:17164409, ECO:0000269|PubMed:23871209, ECO:0000269|PubMed:25538194, ECO:0000269|PubMed:33231615}. Cytoplasm, cytoskeleton, microtubule organizing center {ECO:0000269|PubMed:28656979, ECO:0000269|PubMed:39173637}. Golgi apparatus membrane {ECO:0000269|PubMed:23229815, ECO:0000269|PubMed:30487600}. Endoplasmic reticulum {ECO:0000250|UniProtKB:Q8R4B8}. Mitochondrion {ECO:0000269|PubMed:21124315, ECO:0000269|PubMed:23582325}. Secreted {ECO:0000269|PubMed:24952504}. 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 (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 for the formation of an active inflammasome complex (PubMed:39173637). 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 (PubMed:24952504). Phagocytosis induces lysosomal damage and inflammasome activation in the recipient cells (PubMed:24952504). In the Th2 subset of CD4(+) helper T cells, mainly located in the nucleus (By similarity). Nuclear localization depends upon KPNA2 (By similarity). In the Th1 subset of CD4(+) helper T cells, mainly cytoplasmic (By similarity). {ECO:0000250|UniProtKB:Q8R4B8, ECO:0000269|PubMed:24952504, ECO:0000269|PubMed:30487600, ECO:0000269|PubMed:39173637}.
uniprot
proteins