Q8R4B8 · NLRP3_MOUSE
- ProteinNACHT, LRR and PYD domains-containing protein 3
- GeneNlrp3
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids1033 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
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).
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).
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).
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).
Catalytic activity
- ATP + H2O = ADP + H+ + phosphateThis reaction proceeds in the forward direction.
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).
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).
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).
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).
Features
Showing features for binding site.
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameNACHT, LRR and PYD domains-containing protein 3
- EC number
- Alternative names
Gene names
Organism names
- Organism
- Strains
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus
Accessions
- Primary accessionQ8R4B8
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
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).
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).
Keywords
- Cellular component
Phenotypes & Variants
Disruption phenotype
Knockout mice are fertile and appear healthy when housed in a standard specific pathogen-free environment (PubMed:16407888, PubMed:16407890).
They do not exhibit any increase in serum IL1B after administration of R837 (an analog to guanosine and TLR7 agonist) and/or LPS (PubMed:16407888, PubMed:16407890, PubMed:37001519).
When challenged with LPS, mutant mice are partially resistant to endotoxic shock (PubMed:16407890, PubMed:16546100, PubMed:37001519).
Mutant mice display impaired contact hypersensitivity, a T-cell-mediated cellular immune response to repeated epicutaneous exposure to contact allergens, such as trinitrophenylchloride (PubMed:16546100).
In response to asbestos inhalation, mice show diminished recruitment of inflammatory cells to the lungs, paralleled by lower cytokine production (PubMed:18403674).
In a model of allergic asthma that promotes strictly Th2 responses, mutant animals show less infiltration of eosinophils and lymphocytes into the lungs than their wild-type counterparts, as well as less accumulation of mucus and lymphoid infiltrates (PubMed:26098997).
The concentration of Th2 cell-related cytokines, including IL-5 and IL-4, is also lower in lungs from mutant mice compared to wild-type (PubMed:26098997).
Knockout mice develop insulin (INS) resistance in response to high-fat diet (PubMed:23809162).
Mutants mice are protected from lung injury and cytokine production induced by human SARS coronavirus-2/SARS-CoV-2 N protein (PubMed:34341353).
They do not exhibit any increase in serum IL1B after administration of R837 (an analog to guanosine and TLR7 agonist) and/or LPS (PubMed:16407888, PubMed:16407890, PubMed:37001519).
When challenged with LPS, mutant mice are partially resistant to endotoxic shock (PubMed:16407890, PubMed:16546100, PubMed:37001519).
Mutant mice display impaired contact hypersensitivity, a T-cell-mediated cellular immune response to repeated epicutaneous exposure to contact allergens, such as trinitrophenylchloride (PubMed:16546100).
In response to asbestos inhalation, mice show diminished recruitment of inflammatory cells to the lungs, paralleled by lower cytokine production (PubMed:18403674).
In a model of allergic asthma that promotes strictly Th2 responses, mutant animals show less infiltration of eosinophils and lymphocytes into the lungs than their wild-type counterparts, as well as less accumulation of mucus and lymphoid infiltrates (PubMed:26098997).
The concentration of Th2 cell-related cytokines, including IL-5 and IL-4, is also lower in lungs from mutant mice compared to wild-type (PubMed:26098997).
Knockout mice develop insulin (INS) resistance in response to high-fat diet (PubMed:23809162).
Mutants mice are protected from lung injury and cytokine production induced by human SARS coronavirus-2/SARS-CoV-2 N protein (PubMed:34341353).
Features
Showing features for mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Mutagenesis | 127-130 | In 4KA mutant; abolished binding to phosphatidylinositol 4-phosphate (PtdIns4P) and recruitment to dispersed trans-Golgi network (dTGN) vesicle membranes. | ||||
Sequence: KKKK → AAAA | ||||||
Mutagenesis | 127-143 | 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. | ||||
Sequence: KKKKDYCKMYRRHVRSR → AAAADYCKMYAAHVASA | ||||||
Mutagenesis | 194 | Abolished phosphorylation by JNK1 leading to decreased activation of the NLRP3 inflammasome. | ||||
Sequence: S → A | ||||||
Mutagenesis | 291 | Abolished phosphorylation by PKD/PRKD1, leading to prevent NLRP3 inflammasome activation. | ||||
Sequence: S → A | ||||||
Mutagenesis | 291 | Mimics phosphorylation state; despite this, does not promote activation of the NLRP3 inflammasome. | ||||
Sequence: S → E | ||||||
Mutagenesis | 754 | Increases interaction with NEK7. | ||||
Sequence: G → A or R | ||||||
Mutagenesis | 771-776 | In LRRm3 mutant; abolished ability to form homooligomeric double-ring cages that hide pyrin domains to avoid premature activation. | ||||
Sequence: RLWLGR → ELTLGE | ||||||
Mutagenesis | 781-785 | In LRRm5 mutant; abolished ability to form homooligomeric double-ring cages that hide pyrin domains to avoid premature activation. | ||||
Sequence: HQCCF → ERCCA | ||||||
Mutagenesis | 803 | Mimics phosphorylation state; impaired ability to recruit NEK7, leding to decreased activation of the NLRP3 inflammasome. | ||||
Sequence: S → D | ||||||
Mutagenesis | 809-813 | In LRRm4 mutant; abolished ability to form homooligomeric double-ring cages that hide pyrin domains to avoid premature activation. | ||||
Sequence: DFGIR → RAGIE | ||||||
Mutagenesis | 830 | In LRRm1 mutant; abolished ability to form homooligomeric double-ring cages that hide pyrin domains to avoid premature activation; when associated with C-858. | ||||
Sequence: W → A | ||||||
Mutagenesis | 858 | In LRRm1 mutant; abolished ability to form homooligomeric double-ring cages that hide pyrin domains to avoid premature activation; when associated with A-830. | ||||
Sequence: Y → C | ||||||
Mutagenesis | 970 | 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. | ||||
Sequence: K → E | ||||||
Mutagenesis | 1001 | 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. | ||||
Sequence: Q → R | ||||||
Mutagenesis | 1008-1013 | In LRRm2 mutant; abolished ability to form homooligomeric double-ring cages that hide pyrin domains to avoid premature activation. | ||||
Sequence: NRETKR → REERTKE | ||||||
Mutagenesis | 1029 | 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. | ||||
Sequence: F → A |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 43 variants from UniProt as well as other sources including ClinVar and dbSNP.
Chemistry
PTM/Processing
Features
Showing features for chain, modified residue, disulfide bond, cross-link, lipidation.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000080887 | 1-1033 | NACHT, LRR and PYD domains-containing protein 3 | |||
Sequence: MTSVRCKLAQYLEDLEDVDLKKFKMHLEDYPPEKGCIPVPRGQMEKADHLDLATLMIDFNGEEKAWAMAVWIFAAINRRDLWEKAKKDQPEWNDTCTSHSSMVCQEDSLEEEWMGLLGYLSRISICKKKKDYCKMYRRHVRSRFYSIKDRNARLGESVDLNSRYTQLQLVKEHPSKQEREHELLTIGRTKMRDSPMSSLKLELLFEPEDGHSEPVHTVVFQGAAGIGKTILARKIMLDWALGKLFKDKFDYLFFIHCREVSLRTPRSLADLIVSCWPDPNPPVCKILRKPSRILFLMDGFDELQGAFDEHIGEVCTDWQKAVRGDILLSSLIRKKLLPKASLLITTRPVALEKLQHLLDHPRHVEILGFSEAKRKEYFFKYFSNELQAREAFRLIQENEVLFTMCFIPLVCWIVCTGLKQQMETGKSLAQTSKTTTAVYVFFLSSLLQSRGGIEEHLFSDYLQGLCSLAADGIWNQKILFEECDLRKHGLQKTDVSAFLRMNVFQKEVDCERFYSFSHMTFQEFFAAMYYLLEEEAEGETVRKGPGGCSDLLNRDVKVLLENYGKFEKGYLIFVVRFLFGLVNQERTSYLEKKLSCKISQQVRLELLKWIEVKAKAKKLQWQPSQLELFYCLYEMQEEDFVQSAMDHFPKIEINLSTRMDHVVSSFCIKNCHRVKTLSLGFFHNSPKEEEEERRGGRPLDQVQCVFPDTHVACSSRLVNCCLTSSFCRGLFSSLSTNRSLTELDLSDNTLGDPGMRVLCEALQHPGCNIQRLWLGRCGLSHQCCFDISSVLSSSQKLVELDLSDNALGDFGIRLLCVGLKHLLCNLQKLWLVSCCLTSACCQDLALVLSSNHSLTRLYIGENALGDSGVQVLCEKMKDPQCNLQKLGLVNSGLTSICCSALTSVLKTNQNFTHLYLRSNALGDTGLRLLCEGLLHPDCKLQMLELDNCSLTSHSCWNLSTILTHNHSLRKLNLGNNDLGDLCVVTLCEVLKQQGCLLQSLQLGEMYLNRETKRALEALQEEKPELTIVFEISW | ||||||
Modified residue | 3 | Phosphoserine | ||||
Sequence: S | ||||||
Disulfide bond | 6↔104 | Redox-active | ||||
Sequence: CKLAQYLEDLEDVDLKKFKMHLEDYPPEKGCIPVPRGQMEKADHLDLATLMIDFNGEEKAWAMAVWIFAAINRRDLWEKAKKDQPEWNDTCTSHSSMVC | ||||||
Modified residue | 11 | Phosphotyrosine | ||||
Sequence: Y | ||||||
Modified residue | 132 | Phosphotyrosine; by BTK | ||||
Sequence: Y | ||||||
Modified residue | 136 | Phosphotyrosine; by BTK | ||||
Sequence: Y | ||||||
Modified residue | 145 | Phosphotyrosine; by BTK | ||||
Sequence: Y | ||||||
Modified residue | 157 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 164 | Phosphotyrosine; by BTK | ||||
Sequence: Y | ||||||
Modified residue | 194 | Phosphoserine; by MAPK8 | ||||
Sequence: S | ||||||
Modified residue | 197 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 291 | Phosphoserine; by PKD/PRKD1 | ||||
Sequence: S | ||||||
Modified residue | 330 | Phosphoserine | ||||
Sequence: S | ||||||
Cross-link | 687 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Modified residue | 725 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 732 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 803 | Phosphoserine; by CSNK1A1 | ||||
Sequence: S | ||||||
Lipidation | 834 | S-palmitoyl cysteine | ||||
Sequence: C | ||||||
Lipidation | 835 | S-palmitoyl cysteine | ||||
Sequence: C | ||||||
Lipidation | 841 | S-palmitoyl cysteine | ||||
Sequence: C | ||||||
Modified residue | 858 | Phosphotyrosine | ||||
Sequence: Y | ||||||
Cross-link | 875 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Cross-link | 970 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Modified residue | 1032 | Phosphoserine | ||||
Sequence: S |
Post-translational modification
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).
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).
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.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
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).
Expressed at low levels in resting osteoblasts (at protein level) (PubMed:17907925).
Induction
By activators of Toll-like receptors, such as lipoteichoic acid (LTA) (TLR2), polyinosine-polycytidylic acid (poly(I:C), a synthetic analog of dsRNA) (TLR3) and bacterial lipopolysaccharides (LPS) (TLR4) (PubMed:16546100).
Up-regulated by IL2 via STAT5 signaling (PubMed:26098997).
Slightly up-regulated in osteoblasts after exposure to invasive, but not invasion-defective, strains of Salmonella typhimurium (at protein level) (PubMed:17907925).
Up-regulated by IL2 via STAT5 signaling (PubMed:26098997).
Slightly up-regulated in osteoblasts after exposure to invasive, but not invasion-defective, strains of Salmonella typhimurium (at protein level) (PubMed:17907925).
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).
Gene expression databases
Interaction
Subunit
Sensor component of NLRP3 inflammasomes; inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation (PubMed:34861190).
The core of NLRP3 inflammasomes consists of a signal sensor component (NLRP3), an adapter (PYCARD/ASC), which recruits an effector pro-inflammatory caspase (CASP1 and, possibly, CASP4 and CASP5) (PubMed:24630723).
Homodecamer; inactive NLRP3 forms homodecameric double-ring cages that hide pyrin domains within NACHT-LRR rings to avoid premature activation (PubMed:34861190, PubMed:35254907).
Interacts (via pyrin domain) with PYCARD/ASC (via pyrin domain); interaction is direct (PubMed:17907925, PubMed:30487600).
Interacts (via LRR repeat domain) with NEK7 (via N-terminus); the interaction is required for the formation of the complex NLRP3:PYCARD, oligomerization of PYCARD/ASC and activation of CASP1 (PubMed:26553871, PubMed:26642356, PubMed:26814970, PubMed:34615873, PubMed:37001519).
Interacts (via LRR repeat domain) with NR4A1/Nur77 (via N-terminus); the interaction is direct, requires activation of NR4A1 by its ligands NBRE-containing dsDNA and lipopolysaccharide, and stimulates the association of NLRP3 with NEK7 for non-canonical NLRP3 inflammasome activation (PubMed:37001519).
Interacts with CARD8; leading to inhibit formation of the NLRP3 inflammasome (By similarity).
Interacts with MEFV; this interaction targets NLRP3 to degradation by autophagy, hence preventing excessive IL1B- and IL18-mediated inflammation (By similarity).
Interacts with EIF2AK2/PKR; this interaction requires EIF2AK2 activity, is accompanied by EIF2AK2 autophosphorylation and promotes inflammasome assembly in response to specific stimuli (PubMed:22801494).
Interacts with GBP5 (via DAPIN domain); this interaction promotes inflammasome assembly in response to microbial and soluble, but not crystalline, agents (By similarity).
Interacts with PML (isoform PML-1) (via the leucine-rich repeat (LRR) domain); PML-mediated increase in NLRP3 inflammasome activation does not depend upon this interaction (By similarity).
Interacts (via NACHT domain) with DHX33 (via DEAH box); NLRP3 activation in presence of cytosolic dsRNA is mediated by DHX33 (By similarity).
Interacts (via NACHT and LRR domains) with ARRB2; this interaction is direct and inducible by polyunsaturated fatty acids (PUFAs) (By similarity).
Interacts (via NACHT domain) with DDX3X under both LPS-primed and inflammasome-activating conditions (PubMed:31511697).
Interacts with IRF4 (via the LRR domain); this interaction is direct and is required for optimal IRF4 binding to IL4 promoter and efficient IL4 transactivation during differentiation of Th2 helper T-cells (PubMed:26098997).
Interacts with MAVS; promoting localization to mitochondria and activation of the NLRP3 inflammasome (PubMed:23582325).
Interacts with MARK4; promoting localization of NLRP3 to the microtubule organizing center (MTOC) (PubMed:28656979).
Interacts with TRIM50; this interaction promotes also NLRP3 oligomerization and subsequent inflammasome activation (PubMed:36178239).
Interacts with IRGM; preventing NLRP3 inflammasome assembly and promoting NLRP3 degradation (By similarity).
Interacts (via KFERQ-like motifs) with HSPA8/HSC70; promoting NLRP3 degradation by the chaperone-mediated autophagy pathway (By similarity).
The core of NLRP3 inflammasomes consists of a signal sensor component (NLRP3), an adapter (PYCARD/ASC), which recruits an effector pro-inflammatory caspase (CASP1 and, possibly, CASP4 and CASP5) (PubMed:24630723).
Homodecamer; inactive NLRP3 forms homodecameric double-ring cages that hide pyrin domains within NACHT-LRR rings to avoid premature activation (PubMed:34861190, PubMed:35254907).
Interacts (via pyrin domain) with PYCARD/ASC (via pyrin domain); interaction is direct (PubMed:17907925, PubMed:30487600).
Interacts (via LRR repeat domain) with NEK7 (via N-terminus); the interaction is required for the formation of the complex NLRP3:PYCARD, oligomerization of PYCARD/ASC and activation of CASP1 (PubMed:26553871, PubMed:26642356, PubMed:26814970, PubMed:34615873, PubMed:37001519).
Interacts (via LRR repeat domain) with NR4A1/Nur77 (via N-terminus); the interaction is direct, requires activation of NR4A1 by its ligands NBRE-containing dsDNA and lipopolysaccharide, and stimulates the association of NLRP3 with NEK7 for non-canonical NLRP3 inflammasome activation (PubMed:37001519).
Interacts with CARD8; leading to inhibit formation of the NLRP3 inflammasome (By similarity).
Interacts with MEFV; this interaction targets NLRP3 to degradation by autophagy, hence preventing excessive IL1B- and IL18-mediated inflammation (By similarity).
Interacts with EIF2AK2/PKR; this interaction requires EIF2AK2 activity, is accompanied by EIF2AK2 autophosphorylation and promotes inflammasome assembly in response to specific stimuli (PubMed:22801494).
Interacts with GBP5 (via DAPIN domain); this interaction promotes inflammasome assembly in response to microbial and soluble, but not crystalline, agents (By similarity).
Interacts with PML (isoform PML-1) (via the leucine-rich repeat (LRR) domain); PML-mediated increase in NLRP3 inflammasome activation does not depend upon this interaction (By similarity).
Interacts (via NACHT domain) with DHX33 (via DEAH box); NLRP3 activation in presence of cytosolic dsRNA is mediated by DHX33 (By similarity).
Interacts (via NACHT and LRR domains) with ARRB2; this interaction is direct and inducible by polyunsaturated fatty acids (PUFAs) (By similarity).
Interacts (via NACHT domain) with DDX3X under both LPS-primed and inflammasome-activating conditions (PubMed:31511697).
Interacts with IRF4 (via the LRR domain); this interaction is direct and is required for optimal IRF4 binding to IL4 promoter and efficient IL4 transactivation during differentiation of Th2 helper T-cells (PubMed:26098997).
Interacts with MAVS; promoting localization to mitochondria and activation of the NLRP3 inflammasome (PubMed:23582325).
Interacts with MARK4; promoting localization of NLRP3 to the microtubule organizing center (MTOC) (PubMed:28656979).
Interacts with TRIM50; this interaction promotes also NLRP3 oligomerization and subsequent inflammasome activation (PubMed:36178239).
Interacts with IRGM; preventing NLRP3 inflammasome assembly and promoting NLRP3 degradation (By similarity).
Interacts (via KFERQ-like motifs) with HSPA8/HSC70; promoting NLRP3 degradation by the chaperone-mediated autophagy pathway (By similarity).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | Q8R4B8 | Casp1 P29452 | 2 | EBI-6910832, EBI-489700 | |
BINARY | Q8R4B8 | Eif2ak2 Q03963 | 3 | EBI-6910832, EBI-2603444 | |
BINARY | Q8R4B8 | Nek7 Q9ES74 | 2 | EBI-6910832, EBI-16193749 | |
BINARY | Q8R4B8 | Pycard Q9EPB4 | 7 | EBI-6910832, EBI-6253348 |
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for domain, region, motif, repeat.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 1-91 | Pyrin | ||||
Sequence: MTSVRCKLAQYLEDLEDVDLKKFKMHLEDYPPEKGCIPVPRGQMEKADHLDLATLMIDFNGEEKAWAMAVWIFAAINRRDLWEKAKKDQPE | ||||||
Region | 127-130 | Required for binding to phosphatidylinositol 4-phosphate (PtdIns4P) | ||||
Sequence: KKKK | ||||||
Domain | 136-206 | FISNA | ||||
Sequence: YRRHVRSRFYSIKDRNARLGESVDLNSRYTQLQLVKEHPSKQEREHELLTIGRTKMRDSPMSSLKLELLFE | ||||||
Domain | 216-532 | NACHT | ||||
Sequence: HTVVFQGAAGIGKTILARKIMLDWALGKLFKDKFDYLFFIHCREVSLRTPRSLADLIVSCWPDPNPPVCKILRKPSRILFLMDGFDELQGAFDEHIGEVCTDWQKAVRGDILLSSLIRKKLLPKASLLITTRPVALEKLQHLLDHPRHVEILGFSEAKRKEYFFKYFSNELQAREAFRLIQENEVLFTMCFIPLVCWIVCTGLKQQMETGKSLAQTSKTTTAVYVFFLSSLLQSRGGIEEHLFSDYLQGLCSLAADGIWNQKILFEECDLRKHGLQKTDVSAFLRMNVFQKEVDCERFYSFSHMTFQEFFAAMYYLL | ||||||
Motif | 351-355 | KFERQ-like motif 1 | ||||
Sequence: LEKLQ | ||||||
Motif | 601-605 | KFERQ-like motif 2 | ||||
Sequence: QVRLE | ||||||
Repeat | 739-759 | LRR 1 | ||||
Sequence: SLTELDLSDNTLGDPGMRVLC | ||||||
Repeat | 768-789 | LRR 2 | ||||
Sequence: NIQRLWLGRCGLSHQCCFDISS | ||||||
Motif | 795-799 | KFERQ-like motif 3 | ||||
Sequence: QKLVE | ||||||
Repeat | 796-816 | LRR 3 | ||||
Sequence: KLVELDLSDNALGDFGIRLLC | ||||||
Repeat | 825-846 | LRR 4 | ||||
Sequence: NLQKLWLVSCCLTSACCQDLAL | ||||||
Repeat | 853-873 | LRR 5 | ||||
Sequence: SLTRLYIGENALGDSGVQVLC | ||||||
Repeat | 882-903 | LRR 6 | ||||
Sequence: NLQKLGLVNSGLTSICCSALTS | ||||||
Repeat | 910-930 | LRR 7 | ||||
Sequence: NFTHLYLRSNALGDTGLRLLC | ||||||
Repeat | 939-960 | LRR 8 | ||||
Sequence: KLQMLELDNCSLTSHSCWNLST | ||||||
Repeat | 967-988 | LRR 9 | ||||
Sequence: SLRKLNLGNNDLGDLCVVTLCE | ||||||
Motif | 988-992 | KFERQ-like motif 4 | ||||
Sequence: EVLKQ |
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.
Sequence similarities
Belongs to the NLRP family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence & Isoforms
- Sequence statusComplete
This entry describes 4 isoforms produced by Alternative splicing.
Q8R4B8-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- SynonymsMMIG-1a
- Length1,033
- Mass (Da)118,275
- Last updated2002-06-01 v1
- Checksum5924690966B12117
Q8R4B8-2
- Name2
- SynonymsMMIG-1b
- Differences from canonical
- 888-944: Missing
Q8R4B8-3
- Name3
- SynonymsMMIG-1c
- Differences from canonical
- 774-830: Missing
Q8R4B8-4
- Name4
- SynonymsMMIG-1d
- Differences from canonical
- 830-1033: Missing
Computationally mapped potential isoform sequences
There is 1 potential isoform mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
Q5SXI6 | Q5SXI6_MOUSE | Nlrp3 | 173 |
Features
Showing features for sequence conflict, alternative sequence.
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF486632 EMBL· GenBank· DDBJ | AAL90874.1 EMBL· GenBank· DDBJ | mRNA | ||
AY495376 EMBL· GenBank· DDBJ | AAS75794.1 EMBL· GenBank· DDBJ | mRNA | ||
AY495377 EMBL· GenBank· DDBJ | AAS75795.1 EMBL· GenBank· DDBJ | mRNA | ||
AY337285 EMBL· GenBank· DDBJ | AAR03540.1 EMBL· GenBank· DDBJ | mRNA | ||
AY337292 EMBL· GenBank· DDBJ | AAR03541.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY337286 EMBL· GenBank· DDBJ | AAR03541.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY337287 EMBL· GenBank· DDBJ | AAR03541.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY337288 EMBL· GenBank· DDBJ | AAR03541.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY337289 EMBL· GenBank· DDBJ | AAR03541.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY337290 EMBL· GenBank· DDBJ | AAR03541.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY337291 EMBL· GenBank· DDBJ | AAR03541.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY337299 EMBL· GenBank· DDBJ | AAR03542.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY337293 EMBL· GenBank· DDBJ | AAR03542.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY337294 EMBL· GenBank· DDBJ | AAR03542.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY337295 EMBL· GenBank· DDBJ | AAR03542.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY337296 EMBL· GenBank· DDBJ | AAR03542.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY337297 EMBL· GenBank· DDBJ | AAR03542.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY337298 EMBL· GenBank· DDBJ | AAR03542.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY337306 EMBL· GenBank· DDBJ | AAR03543.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY337300 EMBL· GenBank· DDBJ | AAR03543.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY337301 EMBL· GenBank· DDBJ | AAR03543.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY337302 EMBL· GenBank· DDBJ | AAR03543.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY337303 EMBL· GenBank· DDBJ | AAR03543.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY337304 EMBL· GenBank· DDBJ | AAR03543.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY337305 EMBL· GenBank· DDBJ | AAR03543.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AY355340 EMBL· GenBank· DDBJ | AAR14737.1 EMBL· GenBank· DDBJ | mRNA | ||
KF032621 EMBL· GenBank· DDBJ | AGU01502.1 EMBL· GenBank· DDBJ | mRNA | ||
AL592522 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
BC116174 EMBL· GenBank· DDBJ | AAI16175.1 EMBL· GenBank· DDBJ | mRNA | ||
BC116175 EMBL· GenBank· DDBJ | AAI16176.1 EMBL· GenBank· DDBJ | mRNA |