NLRP3_MOUSE
ID NLRP3_MOUSE Reviewed; 1033 AA.
AC Q8R4B8; Q1JQ87; Q1JQ88; Q6JEL0; T1W2H6;
DT 28-MAR-2003, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2002, sequence version 1.
DT 03-AUG-2022, entry version 181.
DE RecName: Full=NACHT, LRR and PYD domains-containing protein 3 {ECO:0000305};
DE AltName: Full=Cold autoinflammatory syndrome 1 protein homolog;
DE AltName: Full=Cryopyrin;
DE AltName: Full=Mast cell maturation-associated-inducible protein 1;
DE AltName: Full=PYRIN-containing APAF1-like protein 1;
GN Name=Nlrp3 {ECO:0000312|MGI:MGI:2653833};
GN Synonyms=Cias1, Mmig1, Nalp3, Pypaf1;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3 AND 4), AND SUBCELLULAR
RP LOCATION.
RC STRAIN=BALB/cJ;
RX PubMed=14688236; DOI=10.1093/jb/mvg195;
RA Kikuchi-Yanoshita R., Taketomi Y., Koga K., Sugiki T., Atsumi Y., Saito T.,
RA Ishii S., Hisada M., Suzuki-Nishimura T., Uchida M.K., Moon T.-C.,
RA Chang H.-W., Sawada M., Inagaki N., Nagai H., Murakami M., Kudo I.;
RT "Induction of PYPAF1 during in vitro maturation of mouse mast cells.";
RL J. Biochem. 134:699-709(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1), AND TISSUE
RP SPECIFICITY.
RC STRAIN=129/Sv, BALB/cJ, and C57BL/6J;
RX PubMed=15302403; DOI=10.1016/j.gene.2004.05.002;
RA Anderson J.P., Mueller J.L., Rosengren S., Boyle D.L., Schaner P.,
RA Cannon S.B., Goodyear C.S., Hoffman H.M.;
RT "Structural, expression, and evolutionary analysis of mouse CIAS1.";
RL Gene 338:25-34(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC STRAIN=C57BL/6J;
RA Martinon F., Hofmann K., Tschopp J.;
RT "Murine NALPs: a family of proteins involved in inflammation.";
RL Submitted (JUL-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC STRAIN=BALB/cJ;
RA Huang Z.Q., Yu M., Tong S.;
RL Submitted (MAY-2013) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 4).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP FUNCTION, TISSUE SPECIFICITY, INDUCTION BY LPS, DEVELOPMENTAL STAGE, AND
RP DISRUPTION PHENOTYPE.
RX PubMed=16546100; DOI=10.1016/j.immuni.2006.02.004;
RA Sutterwala F.S., Ogura Y., Szczepanik M., Lara-Tejero M.,
RA Lichtenberger G.S., Grant E.P., Bertin J., Coyle A.J., Galan J.E.,
RA Askenase P.W., Flavell R.A.;
RT "Critical role for NALP3/CIAS1/Cryopyrin in innate and adaptive immunity
RT through its regulation of caspase-1.";
RL Immunity 24:317-327(2006).
RN [8]
RP FUNCTION.
RX PubMed=17008311; DOI=10.1074/jbc.m607594200;
RA Kanneganti T.-D., Body-Malapel M., Amer A., Park J.-H., Whitfield J.,
RA Franchi L., Taraporewala Z.F., Miller D., Patton J.T., Inohara N.,
RA Nunez G.;
RT "Critical role for cryopyrin/Nalp3 in activation of caspase-1 in response
RT to viral infection and double-stranded RNA.";
RL J. Biol. Chem. 281:36560-36568(2006).
RN [9]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=16407890; DOI=10.1038/nature04515;
RA Mariathasan S., Weiss D.S., Newton K., McBride J., O'Rourke K.,
RA Roose-Girma M., Lee W.P., Weinrauch Y., Monack D.M., Dixit V.M.;
RT "Cryopyrin activates the inflammasome in response to toxins and ATP.";
RL Nature 440:228-232(2006).
RN [10]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=16407888; DOI=10.1038/nature04517;
RA Kanneganti T.-D., Oezoeren N., Body-Malapel M., Amer A., Park J.-H.,
RA Franchi L., Whitfield J., Barchet W., Colonna M., Vandenabeele P.,
RA Bertin J., Coyle A., Grant E.P., Akira S., Nunez G.;
RT "Bacterial RNA and small antiviral compounds activate caspase-1 through
RT cryopyrin/Nalp3.";
RL Nature 440:233-236(2006).
RN [11]
RP TISSUE SPECIFICITY, INDUCTION BY SALMONELLA, AND INTERACTION WITH PYCARD.
RX PubMed=17907925; DOI=10.1359/jbmr.071002;
RA McCall S.H., Sahraei M., Young A.B., Worley C.S., Duncan J.A., Ting J.P.,
RA Marriott I.;
RT "Osteoblasts express NLRP3, a nucleotide-binding domain and leucine-rich
RT repeat region containing receptor implicated in bacterially induced cell
RT death.";
RL J. Bone Miner. Res. 23:30-40(2008).
RN [12]
RP FUNCTION.
RX PubMed=20802146; DOI=10.4049/jimmunol.1000803;
RA Lamkanfi M., Sarkar A., Vande Walle L., Vitari A.C., Amer A.O.,
RA Wewers M.D., Tracey K.J., Kanneganti T.D., Dixit V.M.;
RT "Inflammasome-dependent release of the alarmin HMGB1 in endotoxemia.";
RL J. Immunol. 185:4385-4392(2010).
RN [13]
RP UBIQUITINATION, AND DEUBIQUITINATION.
RX PubMed=22948162; DOI=10.1074/jbc.m112.407130;
RA Juliana C., Fernandes-Alnemri T., Kang S., Farias A., Qin F., Alnemri E.S.;
RT "Non-transcriptional priming and deubiquitination regulate NLRP3
RT inflammasome activation.";
RL J. Biol. Chem. 287:36617-36622(2012).
RN [14]
RP FUNCTION, AND INTERACTION WITH EIF2AK2.
RX PubMed=22801494; DOI=10.1038/nature11290;
RA Lu B., Nakamura T., Inouye K., Li J., Tang Y., Lundbaeck P.,
RA Valdes-Ferrer S.I., Olofsson P.S., Kalb T., Roth J., Zou Y.,
RA Erlandsson-Harris H., Yang H., Ting J.P., Wang H., Andersson U.,
RA Antoine D.J., Chavan S.S., Hotamisligil G.S., Tracey K.J.;
RT "Novel role of PKR in inflammasome activation and HMGB1 release.";
RL Nature 488:670-674(2012).
RN [15]
RP DISRUPTION PHENOTYPE.
RX PubMed=23809162; DOI=10.1016/j.immuni.2013.05.015;
RA Yan Y., Jiang W., Spinetti T., Tardivel A., Castillo R., Bourquin C.,
RA Guarda G., Tian Z., Tschopp J., Zhou R.;
RT "Omega-3 fatty acids prevent inflammation and metabolic disorder through
RT inhibition of NLRP3 inflammasome activation.";
RL Immunity 38:1154-1163(2013).
RN [16]
RP UBIQUITINATION, AND DEUBIQUITINATION BY BRCC3.
RX PubMed=23246432; DOI=10.1016/j.molcel.2012.11.009;
RA Py B.F., Kim M.S., Vakifahmetoglu-Norberg H., Yuan J.;
RT "Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome
RT activity.";
RL Mol. Cell 49:331-338(2013).
RN [17]
RP SUBCELLULAR LOCATION.
RX PubMed=23502856; DOI=10.1038/ni.2550;
RA Misawa T., Takahama M., Kozaki T., Lee H., Zou J., Saitoh T., Akira S.;
RT "Microtubule-driven spatial arrangement of mitochondria promotes activation
RT of the NLRP3 inflammasome.";
RL Nat. Immunol. 14:454-460(2013).
RN [18]
RP MECHANISM OF INFLAMMASOME ASSEMBLY.
RX PubMed=24630723; DOI=10.1016/j.cell.2014.01.063;
RA Cai X., Chen J., Xu H., Liu S., Jiang Q.X., Halfmann R., Chen Z.J.;
RT "Prion-like polymerization underlies signal transduction in antiviral
RT immune defense and inflammasome activation.";
RL Cell 156:1207-1222(2014).
RN [19]
RP SUBCELLULAR LOCATION, AND SECRETION OF INFLAMMASOME POLYMERS.
RX PubMed=24952505; DOI=10.1038/ni.2913;
RA Franklin B.S., Bossaller L., De Nardo D., Ratter J.M., Stutz A., Engels G.,
RA Brenker C., Nordhoff M., Mirandola S.R., Al-Amoudi A., Mangan M.S.,
RA Zimmer S., Monks B.G., Fricke M., Schmidt R.E., Espevik T., Jones B.,
RA Jarnicki A.G., Hansbro P.M., Busto P., Marshak-Rothstein A., Hornemann S.,
RA Aguzzi A., Kastenmuller W., Latz E.;
RT "The adaptor ASC has extracellular and 'prionoid' activities that propagate
RT inflammation.";
RL Nat. Immunol. 15:727-737(2014).
RN [20]
RP SUBCELLULAR LOCATION.
RX PubMed=24952504; DOI=10.1038/ni.2919;
RA Baroja-Mazo A., Martin-Sanchez F., Gomez A.I., Martinez C.M.,
RA Amores-Iniesta J., Compan V., Barbera-Cremades M., Yaguee J.,
RA Ruiz-Ortiz E., Anton J., Bujan S., Couillin I., Brough D., Arostegui J.I.,
RA Pelegrin P.;
RT "The NLRP3 inflammasome is released as a particulate danger signal that
RT amplifies the inflammatory response.";
RL Nat. Immunol. 15:738-748(2014).
RN [21]
RP FUNCTION IN TH2 CELLS, INTERACTION WITH IRF4, SUBCELLULAR LOCATION,
RP INDUCTION BY IL2, TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, AND DISRUPTION
RP PHENOTYPE.
RX PubMed=26098997; DOI=10.1038/ni.3202;
RA Bruchard M., Rebe C., Derangere V., Togbe D., Ryffel B., Boidot R.,
RA Humblin E., Hamman A., Chalmin F., Berger H., Chevriaux A., Limagne E.,
RA Apetoh L., Vegran F., Ghiringhelli F.;
RT "The receptor NLRP3 is a transcriptional regulator of TH2
RT differentiation.";
RL Nat. Immunol. 16:859-870(2015).
RN [22]
RP FUNCTION, INTERACTION WITH NEK7, AND ACTIVITY REGULATION.
RX PubMed=26814970; DOI=10.1038/nature16959;
RA He Y., Zeng M.Y., Yang D., Motro B., Nunez G.;
RT "NEK7 is an essential mediator of NLRP3 activation downstream of potassium
RT efflux.";
RL Nature 530:354-357(2016).
RN [23]
RP FUNCTION, INTERACTION WITH NEK7, AND MUTAGENESIS OF GLY-754.
RX PubMed=26642356; DOI=10.1038/ni.3333;
RA Shi H., Wang Y., Li X., Zhan X., Tang M., Fina M., Su L., Pratt D.,
RA Bu C.H., Hildebrand S., Lyon S., Scott L., Quan J., Sun Q., Russell J.,
RA Arnett S., Jurek P., Chen D., Kravchenko V.V., Mathison J.C., Moresco E.M.,
RA Monson N.L., Ulevitch R.J., Beutler B.;
RT "NLRP3 activation and mitosis are mutually exclusive events coordinated by
RT NEK7, a new inflammasome component.";
RL Nat. Immunol. 17:250-258(2016).
RN [24]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=28847925; DOI=10.1073/pnas.1702946114;
RA Nakanishi H., Kawashima Y., Kurima K., Chae J.J., Ross A.M.,
RA Pinto-Patarroyo G., Patel S.K., Muskett J.A., Ratay J.S., Chattaraj P.,
RA Park Y.H., Grevich S., Brewer C.C., Hoa M., Kim H.J., Butman J.A.,
RA Broderick L., Hoffman H.M., Aksentijevich I., Kastner D.L.,
RA Goldbach-Mansky R., Griffith A.J.;
RT "mutation and cochlear autoinflammation cause syndromic and nonsyndromic
RT hearing loss DFNA34 responsive to anakinra therapy.";
RL Proc. Natl. Acad. Sci. U.S.A. 114:E7766-E7775(2017).
RN [25]
RP FUNCTION.
RX PubMed=27374331; DOI=10.1016/j.cell.2016.05.076;
RA Wolf A.J., Reyes C.N., Liang W., Becker C., Shimada K., Wheeler M.L.,
RA Cho H.C., Popescu N.I., Coggeshall K.M., Arditi M., Underhill D.M.;
RT "Hexokinase is an innate immune receptor for the detection of bacterial
RT peptidoglycan.";
RL Cell 166:624-636(2016).
RN [26]
RP INTERACTION WITH DDX3X.
RX PubMed=31511697; DOI=10.1038/s41586-019-1551-2;
RA Samir P., Kesavardhana S., Patmore D.M., Gingras S., Malireddi R.K.S.,
RA Karki R., Guy C.S., Briard B., Place D.E., Bhattacharya A., Sharma B.R.,
RA Nourse A., King S.V., Pitre A., Burton A.R., Pelletier S., Gilbertson R.J.,
RA Kanneganti T.D.;
RT "DDX3X acts as a live-or-die checkpoint in stressed cells by regulating
RT NLRP3 inflammasome.";
RL Nature 573:590-594(2019).
RN [27]
RP DISRUPTION PHENOTYPE.
RX PubMed=34341353; DOI=10.1038/s41467-021-25015-6;
RA Pan P., Shen M., Yu Z., Ge W., Chen K., Tian M., Xiao F., Wang Z., Wang J.,
RA Jia Y., Wang W., Wan P., Zhang J., Chen W., Lei Z., Chen X., Luo Z.,
RA Zhang Q., Xu M., Li G., Li Y., Wu J.;
RT "SARS-CoV-2 N protein promotes NLRP3 inflammasome activation to induce
RT hyperinflammation.";
RL Nat. Commun. 12:4664-4664(2021).
CC -!- FUNCTION: As the sensor component of the NLRP3 inflammasome, plays a
CC crucial role in innate immunity and inflammation. In response to
CC pathogens and other damage-associated signals, initiates the formation
CC of the inflammasome polymeric complex, made of NLRP3, PYCARD and CASP1
CC (or possibly CASP4/CASP11). Recruitment of proCASP1 to the inflammasome
CC promotes its activation and CASP1-catalyzed IL1B and IL18 maturation
CC and secretion in the extracellular milieu (PubMed:28847925,
CC PubMed:27374331, PubMed:26642356, PubMed:26814970). Activation of NLRP3
CC inflammasome is also required for HMGB1 secretion (PubMed:22801494).
CC The active cytokines and HMGB1 stimulate inflammatory responses.
CC Inflammasomes can also induce pyroptosis, an inflammatory form of
CC programmed cell death. Under resting conditions, NLRP3 is
CC autoinhibited. NLRP3 activation stimuli include extracellular ATP,
CC reactive oxygen species, K(+) efflux, crystals of monosodium urate or
CC cholesterol, amyloid-beta fibers, environmental or industrial particles
CC and nanoparticles, cytosolic dsRNA, etc (PubMed:26814970). Activation
CC upon, at least, K(+) efflux is mediated by the interaction wit NEK7
CC (PubMed:26814970). Activation in presence of cytosolic dsRNA is
CC mediated by DHX33 (By similarity). Independently of inflammasome
CC activation, regulates the differentiation of T helper 2 (Th2) cells and
CC has a role in Th2 cell-dependent asthma and tumor growth. During Th2
CC differentiation, required for optimal IRF4 binding to IL4 promoter and
CC for IRF4-dependent IL4 transcription. Binds to the consensus DNA
CC sequence 5'-GRRGGNRGAG-3'. May also participate in the transcription of
CC IL5, IL13, GATA3, CCR3, CCR4 and MAF (PubMed:26098997).
CC {ECO:0000250|UniProtKB:Q96P20, ECO:0000269|PubMed:16407888,
CC ECO:0000269|PubMed:16407890, ECO:0000269|PubMed:16546100,
CC ECO:0000269|PubMed:17008311, ECO:0000269|PubMed:22801494,
CC ECO:0000269|PubMed:26098997, ECO:0000269|PubMed:26642356,
CC ECO:0000269|PubMed:26814970, ECO:0000269|PubMed:27374331,
CC ECO:0000269|PubMed:28847925}.
CC -!- ACTIVITY REGULATION: Under resting conditions, NLRP3 is autoinhibited.
CC NLRP3 activation stimuli include extracellular ATP, reactive oxygen
CC species, K(+) efflux, crystals of monosodium urate or cholesterol,
CC amyloid-beta fibers, environmental or industrial particles and
CC nanoparticles, cytosolic dsRNA, etc (PubMed:26814970). Activation upon,
CC at least, K(+) efflux is mediated by the interaction wit NEK7
CC (PubMed:26814970). {ECO:0000269|PubMed:26814970}.
CC -!- SUBUNIT: Sensor component of NLRP3 inflammasomes. Inflammasomes are
CC supramolecular complexes that assemble in the cytosol in response to
CC pathogens and other damage-associated signals and play critical roles
CC in innate immunity and inflammation. The core of NLRP3 inflammasomes
CC consists of a signal sensor component (NLRP3), an adapter (ASC/PYCARD),
CC which recruits an effector pro-inflammatory caspase (CASP1 and,
CC possibly, CASP4 and CASP5) (PubMed:26642356). Within the complex, NLRP3
CC and PYCARD interact via their respective pyrin domains. This
CC interaction initiates speck formation (nucleation) which greatly
CC enhances further addition of soluble PYCARD molecules to the speck in a
CC prion-like polymerization process. NLRP3 localizes at the end of each
CC PYCARD filament. Clustered PYCARD nucleates the formation of CASP1
CC filaments through the interaction of their respective CARD domains,
CC acting as a platform for CASP1 polymerization. CASP1 filament formation
CC increases local enzyme concentration, resulting in trans-autocleavage
CC and activation. Active CASP1 then processes IL1B and IL18 precursors,
CC leading to the release of mature cytokines in the extracellular milieu
CC and inflammatory response. Reconstituted ternary inflammasomes show
CC star-shaped structures, in which multiple filaments, containing CASP1,
CC protrude radially from a single central hub, containing the sensor
CC protein and PYCARD. In this complex, the sensor protein is sub-
CC stoichiometric to PYCARD, and PYCARD is further substoichiometric to
CC CASP1, suggesting amplifications of signal transduction from the
CC sensor, via the adapter, to the effector (By similarity). Interacts
CC with MEFV; this interaction targets NLRP3 to degradation by autophagy,
CC hence preventing excessive IL1B- and IL18-mediated inflammation (By
CC similarity). Interacts with GBP5 (via DAPIN domain); this interaction
CC promotes inflammasome assembly in response to microbial and soluble,
CC but not crystalline, agents (By similarity). Interacts with
CC EIF2AK2/PKR; this interaction requires EIF2AK2 activity, is accompanied
CC by EIF2AK2 autophosphorylation and promotes inflammasome assembly in
CC response to specific stimuli (PubMed:22801494). Interacts with PML
CC (isoform PML-1) (via the LRR region); PML-mediated increase in NLRP3
CC inflammasome activation does not depend upon this interaction. Directly
CC interacts with IRF4 (via LRR region); this interaction is required for
CC optimal IRF4 binding to IL4 promoter and efficient IL4 transactivation
CC during differentiation of Th2 helper T-cells (PubMed:26098997).
CC Interacts (via NACHT domain) with DHX33 (via DEAH box) (By similarity).
CC Interacts with PYDC5 (By similarity). Interacts (via NACHT domain) with
CC DDX3X under both LPS-primed and inflammasome-activating conditions
CC (PubMed:31511697). Interacts (via NACHT and LRR domains) with ARRB2;
CC this interaction is direct and inducible by omega-3 polyunsaturated
CC fatty acids (PUFAs). Interacts (via LRR repeat domain) with NEK7 (via
CC N-terminus); the interaction is required for the formation of the
CC complex NLRP3:PYCARD, oligomerization of PYCARD and activation of CASP1
CC (PubMed:26814970, PubMed:26642356). {ECO:0000250|UniProtKB:Q96P20,
CC ECO:0000269|PubMed:22801494, ECO:0000269|PubMed:26098997,
CC ECO:0000269|PubMed:26642356, ECO:0000269|PubMed:26814970,
CC ECO:0000269|PubMed:31511697}.
CC -!- INTERACTION:
CC Q8R4B8; Q03963: Eif2ak2; NbExp=3; IntAct=EBI-6910832, EBI-2603444;
CC Q8R4B8; Q9ES74: Nek7; NbExp=2; IntAct=EBI-6910832, EBI-16193749;
CC Q8R4B8; Q9EPB4: Pycard; NbExp=3; IntAct=EBI-6910832, EBI-6253348;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:14688236,
CC ECO:0000269|PubMed:23502856, ECO:0000269|PubMed:26098997}. Inflammasome
CC {ECO:0000269|PubMed:14688236, ECO:0000269|PubMed:23502856,
CC ECO:0000269|PubMed:26098997}. Endoplasmic reticulum
CC {ECO:0000269|PubMed:23502856}. Secreted {ECO:0000269|PubMed:24952504}.
CC Nucleus {ECO:0000269|PubMed:26098997}. Note=In macrophages, under
CC resting conditions, mainly located in the cytosol, on the endoplasmic
CC reticulum. After stimulation with inducers of the NLRP3 inflammasome,
CC mitochondria redistribute in the vicinity of the endoplasmic reticulum
CC in the perinuclear region, which results in colocalization of NLRP3 on
CC the endoplasmic reticulum and PYCARD on mitochondria, allowing the
CC activation of inflammasome assembly (PubMed:23502856). After the
CC induction of pyroptosis, inflammasome specks are released into the
CC extracellular space where they can further promote IL1B processing and
CC where they can be engulfed by macrophages. Phagocytosis induces
CC lysosomal damage and inflammasome activation in the recipient cells
CC (PubMed:24952505)(PubMed:24952504). In the Th2 subset of CD4(+) helper
CC T-cells, mainly located in the nucleus. Nuclear localization depends
CC upon KPNA2 (PubMed:26098997). In the Th1 subset of CD4(+) helper T-
CC cells, mainly cytoplasmic (PubMed:26098997).
CC {ECO:0000269|PubMed:23502856, ECO:0000269|PubMed:24952504,
CC ECO:0000269|PubMed:24952505}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1; Synonyms=MMIG-1a;
CC IsoId=Q8R4B8-1; Sequence=Displayed;
CC Name=2; Synonyms=MMIG-1b;
CC IsoId=Q8R4B8-2; Sequence=VSP_014927;
CC Name=3; Synonyms=MMIG-1c;
CC IsoId=Q8R4B8-3; Sequence=VSP_014925;
CC Name=4; Synonyms=MMIG-1d;
CC IsoId=Q8R4B8-4; Sequence=VSP_014926;
CC -!- TISSUE SPECIFICITY: Expressed with high levels in peripheral blood
CC leukocytes, including Th2 lymphocytes and macrophages (PubMed:15302403,
CC PubMed:26098997, PubMed:16546100, PubMed:28847925). Expressed at low
CC levels in resting osteoblasts (at protein level) (PubMed:17907925).
CC {ECO:0000269|PubMed:15302403, ECO:0000269|PubMed:16546100,
CC ECO:0000269|PubMed:17907925, ECO:0000269|PubMed:26098997,
CC ECO:0000269|PubMed:28847925}.
CC -!- DEVELOPMENTAL STAGE: Up-regulated during CD4(+) T-lymphocyte
CC differentiation, in Th0, Th1 and Th2 cells. Not detected in naive
CC CD4(+) T-lymphocytes (at protein level). {ECO:0000269|PubMed:16546100,
CC ECO:0000269|PubMed:26098997}.
CC -!- INDUCTION: By activators of Toll-like receptors, such as lipoteichoic
CC acid (LTA) (TLR2), polyinosine-polycytidylic acid (poly(I:C), a
CC synthetic analog of dsRNA) (TLR3) and bacterial lipopolysaccharides
CC (LPS) (TLR4) (PubMed:16546100). Up-regulated by IL2 via STAT5 signaling
CC (PubMed:26098997). Slightly up-regulated in osteoblasts after exposure
CC to invasive, but not invasion-defective, strains of Salmonella
CC typhimurium (at protein level) (PubMed:17907925).
CC {ECO:0000269|PubMed:16546100, ECO:0000269|PubMed:17907925,
CC ECO:0000269|PubMed:26098997}.
CC -!- DOMAIN: The LRR domain mediates the interaction with IRF4 and PML.
CC {ECO:0000250|UniProtKB:Q96P20, ECO:0000269|PubMed:26098997}.
CC -!- DOMAIN: Intramolecular interactions between NACHT and leucine-rich
CC repeat (LRR) domains may be important for autoinhibition in the absence
CC of activating signal. {ECO:0000250|UniProtKB:Q9EPB4}.
CC -!- DOMAIN: The pyrin domain (also called DAPIN domain or PYD) is involved
CC in PYCARD-binding.
CC -!- PTM: Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked
CC polyubiquitination. Ubiquitination does not lead to degradation, but
CC inhibits inflammasome activation (PubMed:23246432). Deubiquitination is
CC catalyzed by BRCC3 and associated with NLRP3 activation and
CC inflammasome assembly. This process can be induced by the activation of
CC Toll-like receptors (by LPS), through a non-transcriptional pathway
CC dependent on the mitochondrial production of reactive oxygen species,
CC and by ATP. {ECO:0000269|PubMed:22948162, ECO:0000269|PubMed:23246432}.
CC -!- PTM: The disulfide bond in the pyrin domain might play a role in
CC reactive oxygen species-mediated activation.
CC {ECO:0000250|UniProtKB:Q96P20}.
CC -!- DISRUPTION PHENOTYPE: Knockout mice are fertile and appear healthy when
CC housed in a standard specific pathogen-free environment. They do not
CC exhibit any increase in serum IL1B after administration of R837 (an
CC analog to guanosine and TLR7 agonist) and/or LPS (PubMed:16407890)
CC (PubMed:16407888). When challenged with LPS, mutant mice are partially
CC resistant to endotoxic shock (PubMed:16546100) (PubMed:16407890).
CC Mutant mice display impaired contact hypersensitivity, a T-cell-
CC mediated cellular immune response to repeated epicutaneous exposure to
CC contact allergens, such as trinitrophenylchloride (PubMed:16546100). In
CC a model of allergic asthma that promotes strictly Th2 responses, mutant
CC animals show less infiltration of eosinophils and lymphocytes into the
CC lungs than their wild-type counterparts, as well as less accumulation
CC of mucus and lymphoid infiltrates. The concentration of Th2 cell-
CC related cytokines, including IL-5 and IL-4, is also lower in lungs from
CC mutant mice compared to wild-type (PubMed:26098997). Knockout mice
CC develop insulin (INS) resistance in response to high-fat diet. Mutants
CC mice are protected from lung injury and cytokine production induced by
CC human SARS coronavirus-2/SARS-CoV-2 N protein (PubMed:34341353).
CC {ECO:0000269|PubMed:16407888, ECO:0000269|PubMed:16407890,
CC ECO:0000269|PubMed:16546100, ECO:0000269|PubMed:23809162,
CC ECO:0000269|PubMed:26098997, ECO:0000269|PubMed:34341353}.
CC -!- MISCELLANEOUS: Expression is increased in mice with experimental atopic
CC dermatitis.
CC -!- SIMILARITY: Belongs to the NLRP family. {ECO:0000305}.
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DR EMBL; AF486632; AAL90874.1; -; mRNA.
DR EMBL; AY495376; AAS75794.1; -; mRNA.
DR EMBL; AY495377; AAS75795.1; -; mRNA.
DR EMBL; AY337285; AAR03540.1; -; mRNA.
DR EMBL; AY337292; AAR03541.1; -; Genomic_DNA.
DR EMBL; AY337286; AAR03541.1; JOINED; Genomic_DNA.
DR EMBL; AY337287; AAR03541.1; JOINED; Genomic_DNA.
DR EMBL; AY337288; AAR03541.1; JOINED; Genomic_DNA.
DR EMBL; AY337289; AAR03541.1; JOINED; Genomic_DNA.
DR EMBL; AY337290; AAR03541.1; JOINED; Genomic_DNA.
DR EMBL; AY337291; AAR03541.1; JOINED; Genomic_DNA.
DR EMBL; AY337299; AAR03542.1; -; Genomic_DNA.
DR EMBL; AY337293; AAR03542.1; JOINED; Genomic_DNA.
DR EMBL; AY337294; AAR03542.1; JOINED; Genomic_DNA.
DR EMBL; AY337295; AAR03542.1; JOINED; Genomic_DNA.
DR EMBL; AY337296; AAR03542.1; JOINED; Genomic_DNA.
DR EMBL; AY337297; AAR03542.1; JOINED; Genomic_DNA.
DR EMBL; AY337298; AAR03542.1; JOINED; Genomic_DNA.
DR EMBL; AY337306; AAR03543.1; -; Genomic_DNA.
DR EMBL; AY337300; AAR03543.1; JOINED; Genomic_DNA.
DR EMBL; AY337301; AAR03543.1; JOINED; Genomic_DNA.
DR EMBL; AY337302; AAR03543.1; JOINED; Genomic_DNA.
DR EMBL; AY337303; AAR03543.1; JOINED; Genomic_DNA.
DR EMBL; AY337304; AAR03543.1; JOINED; Genomic_DNA.
DR EMBL; AY337305; AAR03543.1; JOINED; Genomic_DNA.
DR EMBL; AY355340; AAR14737.1; -; mRNA.
DR EMBL; KF032621; AGU01502.1; -; mRNA.
DR EMBL; AL592522; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC116174; AAI16175.1; -; mRNA.
DR EMBL; BC116175; AAI16176.1; -; mRNA.
DR CCDS; CCDS24771.1; -. [Q8R4B8-1]
DR RefSeq; NP_665826.1; NM_145827.3. [Q8R4B8-1]
DR RefSeq; XP_006532920.1; XM_006532857.1.
DR RefSeq; XP_006532921.1; XM_006532858.1. [Q8R4B8-1]
DR PDB; 7LFH; EM; 4.20 A; A/B/C/D/E/F/G/H/I/J/K/L=1-1033.
DR PDB; 7VTQ; EM; 3.55 A; A/B/C/D/E/F/G/H/I/J/K/L=1-1033.
DR PDBsum; 7LFH; -.
DR PDBsum; 7VTQ; -.
DR AlphaFoldDB; Q8R4B8; -.
DR SMR; Q8R4B8; -.
DR BioGRID; 229789; 15.
DR ComplexPortal; CPX-4241; NLRP3 inflammasome.
DR CORUM; Q8R4B8; -.
DR DIP; DIP-60132N; -.
DR IntAct; Q8R4B8; 5.
DR STRING; 10090.ENSMUSP00000098707; -.
DR BindingDB; Q8R4B8; -.
DR ChEMBL; CHEMBL3779755; -.
DR iPTMnet; Q8R4B8; -.
DR PhosphoSitePlus; Q8R4B8; -.
DR MaxQB; Q8R4B8; -.
DR PaxDb; Q8R4B8; -.
DR PRIDE; Q8R4B8; -.
DR ProteomicsDB; 293858; -. [Q8R4B8-1]
DR ProteomicsDB; 293859; -. [Q8R4B8-2]
DR ProteomicsDB; 293860; -. [Q8R4B8-3]
DR ProteomicsDB; 293861; -. [Q8R4B8-4]
DR Antibodypedia; 624; 815 antibodies from 46 providers.
DR DNASU; 216799; -.
DR Ensembl; ENSMUST00000079476; ENSMUSP00000078440; ENSMUSG00000032691. [Q8R4B8-1]
DR Ensembl; ENSMUST00000101148; ENSMUSP00000098707; ENSMUSG00000032691. [Q8R4B8-1]
DR GeneID; 216799; -.
DR KEGG; mmu:216799; -.
DR UCSC; uc007jeh.1; mouse. [Q8R4B8-1]
DR CTD; 114548; -.
DR MGI; MGI:2653833; Nlrp3.
DR VEuPathDB; HostDB:ENSMUSG00000032691; -.
DR eggNOG; ENOG502SBIG; Eukaryota.
DR GeneTree; ENSGT00940000162415; -.
DR HOGENOM; CLU_002274_2_0_1; -.
DR InParanoid; Q8R4B8; -.
DR OMA; ETKCALE; -.
DR OrthoDB; 114368at2759; -.
DR PhylomeDB; Q8R4B8; -.
DR Reactome; R-MMU-5689901; Metalloprotease DUBs.
DR Reactome; R-MMU-844456; The NLRP3 inflammasome.
DR BioGRID-ORCS; 216799; 0 hits in 72 CRISPR screens.
DR PRO; PR:Q8R4B8; -.
DR Proteomes; UP000000589; Chromosome 11.
DR RNAct; Q8R4B8; protein.
DR Bgee; ENSMUSG00000032691; Expressed in granulocyte and 46 other tissues.
DR ExpressionAtlas; Q8R4B8; baseline and differential.
DR Genevisible; Q8R4B8; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0000139; C:Golgi membrane; ISO:MGI.
DR GO; GO:0061702; C:inflammasome complex; IDA:MGI.
DR GO; GO:0072559; C:NLRP3 inflammasome complex; IMP:CAFA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0140297; F:DNA-binding transcription factor binding; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0043565; F:sequence-specific DNA binding; IDA:UniProtKB.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IMP:MGI.
DR GO; GO:0002526; P:acute inflammatory response; IDA:MGI.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IDA:UniProtKB.
DR GO; GO:0071224; P:cellular response to peptidoglycan; IMP:CAFA.
DR GO; GO:0098586; P:cellular response to virus; ISO:MGI.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IMP:CAFA.
DR GO; GO:0051607; P:defense response to virus; IMP:MGI.
DR GO; GO:0006954; P:inflammatory response; IDA:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0002523; P:leukocyte migration involved in inflammatory response; IEA:Ensembl.
DR GO; GO:0002674; P:negative regulation of acute inflammatory response; ISO:MGI.
DR GO; GO:0050728; P:negative regulation of inflammatory response; ISO:MGI.
DR GO; GO:0032691; P:negative regulation of interleukin-1 beta production; ISO:MGI.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; ISS:HGNC-UCL.
DR GO; GO:1901223; P:negative regulation of NIK/NF-kappaB signaling; ISS:HGNC-UCL.
DR GO; GO:0044546; P:NLRP3 inflammasome complex assembly; IMP:MGI.
DR GO; GO:0007231; P:osmosensory signaling pathway; IC:ComplexPortal.
DR GO; GO:0002221; P:pattern recognition receptor signaling pathway; IC:ComplexPortal.
DR GO; GO:0043280; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; ISS:HGNC-UCL.
DR GO; GO:0002720; P:positive regulation of cytokine production involved in immune response; IMP:CAFA.
DR GO; GO:0050729; P:positive regulation of inflammatory response; IC:ComplexPortal.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IDA:UniProtKB.
DR GO; GO:0032736; P:positive regulation of interleukin-13 production; IMP:UniProtKB.
DR GO; GO:0032753; P:positive regulation of interleukin-4 production; IDA:UniProtKB.
DR GO; GO:0032754; P:positive regulation of interleukin-5 production; IMP:UniProtKB.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISO:MGI.
DR GO; GO:2000321; P:positive regulation of T-helper 17 cell differentiation; IMP:UniProtKB.
DR GO; GO:2000553; P:positive regulation of T-helper 2 cell cytokine production; IMP:UniProtKB.
DR GO; GO:0045630; P:positive regulation of T-helper 2 cell differentiation; IMP:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0002830; P:positive regulation of type 2 immune response; IMP:UniProtKB.
DR GO; GO:0070269; P:pyroptosis; IC:ComplexPortal.
DR GO; GO:0050727; P:regulation of inflammatory response; IMP:MGI.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0014070; P:response to organic cyclic compound; IEA:Ensembl.
DR Gene3D; 1.10.533.10; -; 1.
DR Gene3D; 3.40.50.300; -; 1.
DR Gene3D; 3.80.10.10; -; 1.
DR InterPro; IPR004020; DAPIN.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR InterPro; IPR001611; Leu-rich_rpt.
DR InterPro; IPR032675; LRR_dom_sf.
DR InterPro; IPR029495; NACHT-assoc.
DR InterPro; IPR007111; NACHT_NTPase.
DR InterPro; IPR041267; NLRP_HD2.
DR InterPro; IPR041075; NOD2_WH.
DR InterPro; IPR027417; P-loop_NTPase.
DR Pfam; PF14484; FISNA; 1.
DR Pfam; PF13516; LRR_6; 5.
DR Pfam; PF05729; NACHT; 1.
DR Pfam; PF17776; NLRC4_HD2; 1.
DR Pfam; PF17779; NOD2_WH; 1.
DR Pfam; PF02758; PYRIN; 1.
DR SMART; SM01288; FISNA; 1.
DR SMART; SM01289; PYRIN; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR PROSITE; PS50824; DAPIN; 1.
DR PROSITE; PS51450; LRR; 5.
DR PROSITE; PS50837; NACHT; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Activator; Alternative splicing; ATP-binding; Cytoplasm;
KW Disulfide bond; Endoplasmic reticulum; Immunity; Inflammasome;
KW Inflammatory response; Innate immunity; Leucine-rich repeat;
KW Nucleotide-binding; Nucleus; Reference proteome; Repeat; Secreted;
KW Transcription; Transcription regulation; Ubl conjugation.
FT CHAIN 1..1033
FT /note="NACHT, LRR and PYD domains-containing protein 3"
FT /id="PRO_0000080887"
FT DOMAIN 1..91
FT /note="Pyrin"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00061"
FT DOMAIN 216..532
FT /note="NACHT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00136"
FT REPEAT 739..759
FT /note="LRR 1"
FT REPEAT 768..789
FT /note="LRR 2"
FT REPEAT 796..816
FT /note="LRR 3"
FT REPEAT 825..846
FT /note="LRR 4"
FT REPEAT 853..873
FT /note="LRR 5"
FT REPEAT 882..903
FT /note="LRR 6"
FT REPEAT 910..930
FT /note="LRR 7"
FT REPEAT 939..960
FT /note="LRR 8"
FT REPEAT 967..988
FT /note="LRR 9"
FT BINDING 222..229
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00136"
FT DISULFID 6..104
FT /note="Redox-active"
FT /evidence="ECO:0000250|UniProtKB:Q96P20"
FT VAR_SEQ 774..830
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14688236"
FT /id="VSP_014925"
FT VAR_SEQ 830..1033
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:14688236,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_014926"
FT VAR_SEQ 888..944
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14688236"
FT /id="VSP_014927"
FT MUTAGEN 754
FT /note="G->A,R: Increases interaction with NEK7."
FT /evidence="ECO:0000269|PubMed:26642356"
FT CONFLICT 491
FT /note="Q -> R (in Ref. 4; AGU01502)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1033 AA; 118275 MW; 5924690966B12117 CRC64;
MTSVRCKLAQ YLEDLEDVDL KKFKMHLEDY PPEKGCIPVP RGQMEKADHL DLATLMIDFN
GEEKAWAMAV WIFAAINRRD LWEKAKKDQP EWNDTCTSHS SMVCQEDSLE EEWMGLLGYL
SRISICKKKK DYCKMYRRHV RSRFYSIKDR NARLGESVDL NSRYTQLQLV KEHPSKQERE
HELLTIGRTK MRDSPMSSLK LELLFEPEDG HSEPVHTVVF QGAAGIGKTI LARKIMLDWA
LGKLFKDKFD YLFFIHCREV SLRTPRSLAD LIVSCWPDPN PPVCKILRKP SRILFLMDGF
DELQGAFDEH IGEVCTDWQK AVRGDILLSS LIRKKLLPKA SLLITTRPVA LEKLQHLLDH
PRHVEILGFS EAKRKEYFFK YFSNELQARE AFRLIQENEV LFTMCFIPLV CWIVCTGLKQ
QMETGKSLAQ TSKTTTAVYV FFLSSLLQSR GGIEEHLFSD YLQGLCSLAA DGIWNQKILF
EECDLRKHGL QKTDVSAFLR MNVFQKEVDC ERFYSFSHMT FQEFFAAMYY LLEEEAEGET
VRKGPGGCSD LLNRDVKVLL ENYGKFEKGY LIFVVRFLFG LVNQERTSYL EKKLSCKISQ
QVRLELLKWI EVKAKAKKLQ WQPSQLELFY CLYEMQEEDF VQSAMDHFPK IEINLSTRMD
HVVSSFCIKN CHRVKTLSLG FFHNSPKEEE EERRGGRPLD QVQCVFPDTH VACSSRLVNC
CLTSSFCRGL FSSLSTNRSL TELDLSDNTL GDPGMRVLCE ALQHPGCNIQ RLWLGRCGLS
HQCCFDISSV LSSSQKLVEL DLSDNALGDF GIRLLCVGLK HLLCNLQKLW LVSCCLTSAC
CQDLALVLSS NHSLTRLYIG ENALGDSGVQ VLCEKMKDPQ CNLQKLGLVN SGLTSICCSA
LTSVLKTNQN FTHLYLRSNA LGDTGLRLLC EGLLHPDCKL QMLELDNCSL TSHSCWNLST
ILTHNHSLRK LNLGNNDLGD LCVVTLCEVL KQQGCLLQSL QLGEMYLNRE TKRALEALQE
EKPELTIVFE ISW
