NLRP6_MOUSE
ID NLRP6_MOUSE Reviewed; 869 AA.
AC Q91WS2; C9W978; F8UKQ6; Q67EY0; Q8K0L4;
DT 28-FEB-2003, integrated into UniProtKB/Swiss-Prot.
DT 21-AUG-2007, sequence version 3.
DT 03-AUG-2022, entry version 162.
DE RecName: Full=NACHT, LRR and PYD domains-containing protein 6 {ECO:0000305};
DE AltName: Full=Angiotensin II/vasopressin receptor {ECO:0000303|PubMed:20923861};
DE AltName: Full=Non-angiotensin-vasopressin receptor {ECO:0000303|PubMed:20923861};
DE Short=Non-AVR {ECO:0000303|PubMed:20923861};
DE AltName: Full=PYRIN-containing APAF1-like protein 5-like {ECO:0000303|PubMed:12633874};
GN Name=Nlrp6 {ECO:0000303|PubMed:21593405, ECO:0000312|MGI:MGI:2141990};
GN Synonyms=Nalp6 {ECO:0000303|Ref.5}, Navr {ECO:0000303|PubMed:20923861},
GN Pypaf5 {ECO:0000303|PubMed:12633874};
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] (ISOFORM 1), AND DISRUPTION PHENOTYPE.
RC STRAIN=C57BL/6J; TISSUE=Kidney;
RX PubMed=20923861; DOI=10.1152/physiolgenomics.00154.2010;
RA Herrera V.L., Bagamasbad P., Decano J.L., Ruiz-Opazo N.;
RT "AVR/NAVR deficiency lowers blood pressure and differentially affects
RT urinary concentrating ability, cognition, and anxiety-like behavior in male
RT and female mice.";
RL Physiol. Genomics 43:32-42(2011).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), FUNCTION, TISSUE SPECIFICITY, AND
RP DISRUPTION PHENOTYPE.
RX PubMed=21593405; DOI=10.1073/pnas.1100981108;
RA Normand S., Delanoye-Crespin A., Bressenot A., Huot L., Grandjean T.,
RA Peyrin-Biroulet L., Lemoine Y., Hot D., Chamaillard M.;
RT "Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls
RT epithelial self-renewal and colorectal carcinogenesis upon injury.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:9601-9606(2011).
RN [3]
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 [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Kidney;
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 [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
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 [6]
RP IDENTIFICATION OF MAMMALIAN ORTHOLOGS OF NALP6.
RX PubMed=12633874; DOI=10.1016/s0014-5793(03)00161-3;
RA Albrecht M., Domingues F.S., Schreiber S., Lengauer T.;
RT "Identification of mammalian orthologs associates PYPAF5 with distinct
RT functional roles.";
RL FEBS Lett. 538:173-177(2003).
RN [7]
RP FUNCTION, DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY.
RX PubMed=21565393; DOI=10.1016/j.cell.2011.04.022;
RA Elinav E., Strowig T., Kau A.L., Henao-Mejia J., Thaiss C.A., Booth C.J.,
RA Peaper D.R., Bertin J., Eisenbarth S.C., Gordon J.I., Flavell R.A.;
RT "NLRP6 inflammasome regulates colonic microbial ecology and risk for
RT colitis.";
RL Cell 145:745-757(2011).
RN [8]
RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=21543645; DOI=10.4049/jimmunol.1100412;
RA Chen G.Y., Liu M., Wang F., Bertin J., Nunez G.;
RT "A functional role for nlrp6 in intestinal inflammation and
RT tumorigenesis.";
RL J. Immunol. 186:7187-7194(2011).
RN [9]
RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=22763455; DOI=10.1038/nature11250;
RA Anand P.K., Malireddi R.K., Lukens J.R., Vogel P., Bertin J., Lamkanfi M.,
RA Kanneganti T.D.;
RT "NLRP6 negatively regulates innate immunity and host defence against
RT bacterial pathogens.";
RL Nature 488:389-393(2012).
RN [10]
RP INDUCTION BY CRH AND ROSIGLITAZONE.
RX PubMed=23470617; DOI=10.1053/j.gastro.2013.02.038;
RA Sun Y., Zhang M., Chen C.C., Gillilland M. III, Sun X., El-Zaatari M.,
RA Huffnagle G.B., Young V.B., Zhang J., Hong S.C., Chang Y.M., Gumucio D.L.,
RA Owyang C., Kao J.Y.;
RT "Stress-induced corticotropin-releasing hormone-mediated NLRP6 inflammasome
RT inhibition and transmissible enteritis in mice.";
RL Gastroenterology 144:1478-1487(2013).
RN [11]
RP FUNCTION.
RX PubMed=23696660; DOI=10.1073/pnas.1307575110;
RA Hu B., Elinav E., Huber S., Strowig T., Hao L., Hafemann A., Jin C.,
RA Wunderlich C., Wunderlich T., Eisenbarth S.C., Flavell R.A.;
RT "Microbiota-induced activation of epithelial IL-6 signaling links
RT inflammasome-driven inflammation with transmissible cancer.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:9862-9867(2013).
RN [12]
RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=24581500; DOI=10.1016/j.cell.2014.01.026;
RA Wlodarska M., Thaiss C.A., Nowarski R., Henao-Mejia J., Zhang J.P.,
RA Brown E.M., Frankel G., Levy M., Katz M.N., Philbrick W.M., Elinav E.,
RA Finlay B.B., Flavell R.A.;
RT "NLRP6 inflammasome orchestrates the colonic host-microbial interface by
RT regulating goblet cell mucus secretion.";
RL Cell 156:1045-1059(2014).
RN [13]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=26638072; DOI=10.1016/j.cell.2015.10.048;
RA Levy M., Thaiss C.A., Zeevi D., Dohnalova L., Zilberman-Schapira G.,
RA Mahdi J.A., David E., Savidor A., Korem T., Herzig Y., Pevsner-Fischer M.,
RA Shapiro H., Christ A., Harmelin A., Halpern Z., Latz E., Flavell R.A.,
RA Amit I., Segal E., Elinav E.;
RT "Microbiota-modulated metabolites shape the intestinal microenvironment by
RT regulating NLRP6 inflammasome signaling.";
RL Cell 163:1428-1443(2015).
RN [14]
RP FUNCTION, DISRUPTION PHENOTYPE, AND DEVELOPMENTAL STAGE.
RX PubMed=26253422; DOI=10.1186/s12974-015-0367-8;
RA Ydens E., Demon D., Lornet G., De Winter V., Timmerman V., Lamkanfi M.,
RA Janssens S.;
RT "Nlrp6 promotes recovery after peripheral nerve injury independently of
RT inflammasomes.";
RL J. Neuroinflamm. 12:143-143(2015).
RN [15]
RP FUNCTION, DISRUPTION PHENOTYPE, AND INTERACTION WITH DHX15.
RX PubMed=26494172; DOI=10.1126/science.aab3145;
RA Wang P., Zhu S., Yang L., Cui S., Pan W., Jackson R., Zheng Y.,
RA Rongvaux A., Sun Q., Yang G., Gao S., Lin R., You F., Flavell R.,
RA Fikrig E.;
RT "Nlrp6 regulates intestinal antiviral innate immunity.";
RL Science 350:826-830(2015).
RN [16]
RP FUNCTION.
RX PubMed=27339979; DOI=10.1126/science.aaf7419;
RA Birchenough G.M., Nystroem E.E., Johansson M.E., Hansson G.C.;
RT "A sentinel goblet cell guards the colonic crypt by triggering Nlrp6-
RT dependent Muc2 secretion.";
RL Science 352:1535-1542(2016).
RN [17]
RP FUNCTION.
RX PubMed=28445725; DOI=10.1016/j.celrep.2017.03.080;
RA Seregin S.S., Golovchenko N., Schaf B., Chen J., Pudlo N.A., Mitchell J.,
RA Baxter N.T., Zhao L., Schloss P.D., Martens E.C., Eaton K.A., Chen G.Y.;
RT "NLRP6 Protects Il10-/- Mice from Colitis by Limiting Colonization of
RT Akkermansia muciniphila.";
RL Cell Rep. 19:733-745(2017).
RN [18]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=29281815; DOI=10.1016/j.celrep.2017.12.026;
RA Lemire P., Robertson S.J., Maughan H., Tattoli I., Streutker C.J.,
RA Platnich J.M., Muruve D.A., Philpott D.J., Girardin S.E.;
RT "The NLR protein NLRP6 does not impact gut microbiota composition.";
RL Cell Rep. 21:3653-3661(2017).
RN [19]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=29281837; DOI=10.1016/j.celrep.2017.12.027;
RA Galvez E.J.C., Iljazovic A., Gronow A., Flavell R., Strowig T.;
RT "Shaping of intestinal microbiota in Nlrp6- and Rag2-deficient mice depends
RT on community structure.";
RL Cell Rep. 21:3914-3926(2017).
RN [20]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=28801232; DOI=10.1016/j.immuni.2017.07.011;
RA Mamantopoulos M., Ronchi F., Van Hauwermeiren F., Vieira-Silva S.,
RA Yilmaz B., Martens L., Saeys Y., Drexler S.K., Yazdi A.S., Raes J.,
RA Lamkanfi M., McCoy K.D., Wullaert A.;
RT "Nlrp6- and ASC-dependent inflammasomes do not shape the commensal gut
RT microbiota composition.";
RL Immunity 47:339-348(2017).
RN [21]
RP FUNCTION.
RX PubMed=30392956; DOI=10.1016/j.cell.2018.09.047;
RA Hara H., Seregin S.S., Yang D., Fukase K., Chamaillard M., Alnemri E.S.,
RA Inohara N., Chen G.Y., Nunez G.;
RT "The NLRP6 inflammasome recognizes lipoteichoic acid and regulates Gram-
RT positive pathogen infection.";
RL Cell 175:1651-1664(2018).
RN [22]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=30248149; DOI=10.1371/journal.ppat.1007308;
RA Ghimire L., Paudel S., Jin L., Baral P., Cai S., Jeyaseelan S.;
RT "NLRP6 negatively regulates pulmonary host defense in Gram-positive
RT bacterial infection through modulating neutrophil recruitment and
RT function.";
RL PLoS Pathog. 14:e1007308-e1007308(2018).
RN [23]
RP FUNCTION, UBIQUITINATION, AND INTERACTION WITH PYCARD.
RX PubMed=32424362; DOI=10.1038/s41590-020-0681-x;
RA Mukherjee S., Kumar R., Tsakem Lenou E., Basrur V., Kontoyiannis D.L.,
RA Ioakeimidis F., Mosialos G., Theiss A.L., Flavell R.A., Venuprasad K.;
RT "Deubiquitination of NLRP6 inflammasome by Cyld critically regulates
RT intestinal inflammation.";
RL Nat. Immunol. 21:626-635(2020).
RN [24]
RP FUNCTION, SUBCELLULAR LOCATION, DOMAIN, INTERACTION WITH PYCARD, AND
RP MUTAGENESIS OF 170-ARG--ARG-173 AND 350-LYS--LYS-354.
RX PubMed=34678144; DOI=10.1016/j.cell.2021.09.032;
RA Shen C., Li R., Negro R., Cheng J., Vora S.M., Fu T.M., Wang A., He K.,
RA Andreeva L., Gao P., Tian Z., Flavell R.A., Zhu S., Wu H.;
RT "Phase separation drives RNA virus-induced activation of the NLRP6
RT inflammasome.";
RL Cell 184:5759-5774(2021).
RN [25]
RP FUNCTION.
RX PubMed=33918100; DOI=10.3390/ijms22083876;
RA Xu D., Wu X., Peng L., Chen T., Huang Q., Wang Y., Ye C., Peng Y., Hu D.,
RA Fang R.;
RT "The Critical Role of NLRP6 Inflammasome in Streptococcus pneumoniae
RT Infection In Vitro and In Vivo.";
RL Int. J. Mol. Sci. 22:0-0(2021).
RN [26]
RP FUNCTION.
RX PubMed=33230225; DOI=10.1038/s41385-020-00357-4;
RA Cai S., Paudel S., Jin L., Ghimire L., Taylor C.M., Wakamatsu N.,
RA Bhattarai D., Jeyaseelan S.;
RT "NLRP6 modulates neutrophil homeostasis in bacterial pneumonia-derived
RT sepsis.";
RL Mucosal Immunol. 14:574-584(2021).
RN [27]
RP FUNCTION.
RX PubMed=33617596; DOI=10.1371/journal.pntd.0009171;
RA Rungue M., Melo V., Martins D., Campos P.C., Leles G., Galvao I.,
RA Mendes V., Aganetti M., Pedersen A., Assis N.R.G., Santos R., Cassali G.D.,
RA Godard A.L.B., Martins F.S., Oliveira S.C., Vieira A.T.;
RT "NLRP6-associated host microbiota composition impacts in the intestinal
RT barrier to systemic dissemination of Brucella abortus.";
RL PLoS Negl. Trop. Dis. 15:e0009171-e0009171(2021).
RN [28]
RP FUNCTION.
RX PubMed=33372132; DOI=10.1073/pnas.2007807118;
RA Sateriale A., Gullicksrud J.A., Engiles J.B., McLeod B.I., Kugler E.M.,
RA Henao-Mejia J., Zhou T., Ring A.M., Brodsky I.E., Hunter C.A., Striepen B.;
RT "The intestinal parasite Cryptosporidium is controlled by an enterocyte
RT intrinsic inflammasome that depends on NLRP6.";
RL Proc. Natl. Acad. Sci. U.S.A. 118:0-0(2021).
CC -!- FUNCTION: Acts as the sensor component of the NLRP6 inflammasome, which
CC mediates inflammasome activation in response to various pathogen-
CC associated signals, leading to maturation and secretion of IL1B and
CC IL18 (PubMed:21593405, PubMed:30392956, PubMed:32424362,
CC PubMed:34678144). Inflammasomes are supramolecular complexes that
CC assemble in the cytosol in response to pathogens and other damage-
CC associated signals and play critical roles in innate immunity and
CC inflammation (PubMed:30392956). Acts as a recognition receptor (PRR):
CC recognizes and binds specific pathogens and other damage-associated
CC signals, such as lipoteichoic acid (LTA), a cell-wall component of
CC Gram-positive bacteria, or double stranded RNA (dsRNA)
CC (PubMed:26494172, PubMed:30392956, PubMed:34678144). May also recognize
CC and bind lipopolysaccharide (LPS), a major component of the outer
CC membrane of Gram-negative bacteria; however, LPS is probably not a
CC major activator of the NLRP6 inflammasome (PubMed:34678144). Following
CC LTA- or dsRNA-binding, NLRP6 undergoes liquid-liquid phase separation
CC (LLPS), enhancing multivalent interactions, an essential step for the
CC formation of the NLRP6 inflammasome polymeric complex
CC (PubMed:34678144). The NLRP6 inflammasome acts by promoting recruitment
CC of effector pro-inflammatory caspases (CASP1 and/or CASP4) that
CC catalyze maturation and secretion of IL1B and IL18 in the extracellular
CC milieu (PubMed:30392956). The NLRP6 inflammasome plays a central role
CC in the maintenance of epithelial integrity and host defense against
CC microbial infections in the intestine (PubMed:21565393,
CC PubMed:22763455, PubMed:23696660, PubMed:26638072, PubMed:28445725,
CC PubMed:30392956). Required to restrict infection against Gram-positive
CC bacteria by recognizing lipoteichoic acid (LTA), leading to recruitment
CC of CASP4 and CASP1, and subsequent maturation and secretion of IL1B and
CC IL18 (PubMed:30392956). Involved in intestinal antiviral innate
CC immunity together with DHX15: recognizes and binds viral dsRNA to
CC restrict infection by enteric viruses through the interferon pathway
CC and GSDMD-dependent release of IL18 (PubMed:26494172, PubMed:34678144).
CC Required to prevent infection by the apicomplexan parasite C.tyzzeri in
CC enterocytes by promoting GSDMD-dependent release of IL18
CC (PubMed:33372132). The NLRP6 inflammasome may also regulate the gut
CC microbiota composition by acting as a sensor of microbiota-associated
CC metabolites to form a PYCARD/ASC-dependent inflammasome for downstream
CC IL18 release and secretion of antimicrobial peptides (PubMed:21565393,
CC PubMed:22763455, PubMed:26638072, PubMed:33617596). Its role in the
CC regulation of the gut microbiota composition is however subject to
CC discussion (PubMed:29281815, PubMed:29281837, PubMed:28801232).
CC Essential for gut mucosal self-renewal and proliferation
CC (PubMed:21593405, PubMed:21543645, PubMed:21565393). Regulate mucus
CC secretion in an inflammasome- and autophagy-dependent manner to prevent
CC invasion by enteric bacteria (PubMed:24581500, PubMed:27339979). During
CC systemic bacterial infections, the NLRP6 inflammasome negatively
CC regulates neutrophil recruitment and neutrophil extracellular traps
CC (NETs) formation (PubMed:22763455, PubMed:30248149, PubMed:33918100,
CC PubMed:33230225). May promote peripheral nerve recovery following
CC injury via an inflammasome-independent mechanism (PubMed:26253422).
CC {ECO:0000269|PubMed:21543645, ECO:0000269|PubMed:21565393,
CC ECO:0000269|PubMed:21593405, ECO:0000269|PubMed:22763455,
CC ECO:0000269|PubMed:23696660, ECO:0000269|PubMed:24581500,
CC ECO:0000269|PubMed:26253422, ECO:0000269|PubMed:26494172,
CC ECO:0000269|PubMed:26638072, ECO:0000269|PubMed:27339979,
CC ECO:0000269|PubMed:28445725, ECO:0000269|PubMed:28801232,
CC ECO:0000269|PubMed:29281815, ECO:0000269|PubMed:29281837,
CC ECO:0000269|PubMed:30248149, ECO:0000269|PubMed:30392956,
CC ECO:0000269|PubMed:32424362, ECO:0000269|PubMed:33230225,
CC ECO:0000269|PubMed:33372132, ECO:0000269|PubMed:33617596,
CC ECO:0000269|PubMed:33918100, ECO:0000269|PubMed:34678144}.
CC -!- SUBUNIT: Homomultimer; forms the NLRP6 inflammasome polymeric complex,
CC a filament composed of homopolymers in response to pathogens and other
CC damage-associated signals (PubMed:34678144). The core of NLRP6
CC inflammasomes consists of a signal sensor component (NLRP6), an adapter
CC (PYCARD/ASC), which recruits effector pro-inflammatory caspases (CASP1
CC and CASP4) (PubMed:34678144). Interacts (via pyrin domain) with
CC PYCARD/ASC (via pyrin domain); interaction takes place following NLRP6
CC activation and formation of liquid-liquid phase separation (LLPS),
CC initiating nucleation which greatly enhances further addition of
CC soluble PYCARD/ASC molecules to the speck in a prion-like
CC polymerization process (PubMed:32424362, PubMed:34678144). Clustered
CC PYCARD/ASC nucleates the formation of CASP1 (or possibly CASP4)
CC filaments through the interaction of their respective CARD domains,
CC acting as a platform for CASP1 polymerization (PubMed:34678144). CASP1
CC filament formation increases local enzyme concentration, resulting in
CC trans-autocleavage and activation (PubMed:34678144). Active CASP1 then
CC processes IL1B and IL18 precursors, leading to the release of mature
CC cytokines in the extracellular milieu and inflammatory response
CC (PubMed:34678144). Interacts with DHX15 (PubMed:26494172).
CC {ECO:0000269|PubMed:26494172, ECO:0000269|PubMed:32424362,
CC ECO:0000269|PubMed:34678144}.
CC -!- INTERACTION:
CC Q91WS2; O35286: Dhx15; NbExp=2; IntAct=EBI-16182145, EBI-8322087;
CC Q91WS2-1; O43143: DHX15; Xeno; NbExp=2; IntAct=EBI-16182226, EBI-1237044;
CC Q91WS2-1; Q7Z434-1: MAVS; Xeno; NbExp=2; IntAct=EBI-16182226, EBI-15577799;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q63035}.
CC Inflammasome {ECO:0000269|PubMed:30248149,
CC ECO:0000269|PubMed:34678144}.
CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Cytoplasm
CC {ECO:0000250|UniProtKB:Q63035}. Inflammasome
CC {ECO:0000250|UniProtKB:P59044}. Cell membrane
CC {ECO:0000250|UniProtKB:Q63035}. Nucleus membrane
CC {ECO:0000250|UniProtKB:Q63035}.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Cytoplasm
CC {ECO:0000250|UniProtKB:Q63035}. Cell membrane
CC {ECO:0000250|UniProtKB:Q63035}. Note=Predominantly expressed in the
CC cell membrane. {ECO:0000250|UniProtKB:Q63035}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative promoter usage, Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=NAVR {ECO:0000303|PubMed:20923861};
CC IsoId=Q91WS2-1; Sequence=Displayed;
CC Name=2; Synonyms=Angiotensin-vasopressin receptor
CC {ECO:0000303|PubMed:20923861}, AVR {ECO:0000303|PubMed:20923861};
CC IsoId=Q91WS2-2; Sequence=VSP_042301;
CC Name=3;
CC IsoId=Q91WS2-3; Sequence=VSP_057971;
CC -!- TISSUE SPECIFICITY: Highly expressed in the gastrointestinal tract,
CC predominantly in colonic myofibroblasts and in colonic epithelial and
CC endothelial cells. Within the intestinal mucosa, highly expressed by
CC goblet cells. Also expressed in hepatocytes and in immune cells,
CC including CD4(+) and CD8(+) T-cells, dendritic cells, mastocytes and
CC peritoneal macrophages, as well as in lung, kidney, bladder and gonads.
CC {ECO:0000269|PubMed:21543645, ECO:0000269|PubMed:21565393,
CC ECO:0000269|PubMed:21593405, ECO:0000269|PubMed:22763455,
CC ECO:0000269|PubMed:24581500}.
CC -!- DEVELOPMENTAL STAGE: Up-regulated transiently following sterile or LPS-
CC induced sciatic nerve injury with a peak after 4 hours.
CC {ECO:0000269|PubMed:26253422}.
CC -!- INDUCTION: Up-regulated by rosiglitazone, a PPARG agonist, in CT26
CC cells. Down-regulated by CRH during water-avoidance stress.
CC {ECO:0000269|PubMed:23470617}.
CC -!- DOMAIN: The poly-Lys disordered region (350-354) mediates the formation
CC of liquid-liquid phase separation (LLPS), an essential step for
CC nucleation and formation of the NLRP6 inflammasome complex.
CC {ECO:0000269|PubMed:34678144}.
CC -!- PTM: Polyubiquitinated with 'Lys-63'-linked chains, promoting the
CC interaction with PYCARD/ASC and formation of the NLRP6 inflammasome
CC (PubMed:32424362). Deubiquitination by CYLD decreases the interaction
CC with PYCARD/ASC (PubMed:32424362). {ECO:0000269|PubMed:32424362}.
CC -!- DISRUPTION PHENOTYPE: Knockout mice are born at the expected Mendelian
CC rate with no morphological abnormalities (PubMed:20923861,
CC PubMed:21593405). They are characterized by spontaneous intestinal
CC hyperplasia, inflammatory cell recruitment, exacerbation of chemical
CC colitis induced by exposure to dextran sodium sulfate (DSS) and develop
CC higher tumor loads in response to a combined treatment with the
CC alkylating procarcinogen azoxymethane (AOM) and DSS (PubMed:21593405,
CC PubMed:21543645, PubMed:21565393, PubMed:26638072). The colitogenic
CC phenotype is associated with altered microbiota and is transmissible to
CC cohoused wild-type mice, both early in postnatal life and during
CC adulthood (PubMed:22763455, PubMed:21565393, PubMed:26638072). The
CC effect on microbiota composition is however unclear, since a number of
CC reports do not observe any difference in microbiota composition between
CC wild-type and knockout mice (PubMed:29281815, PubMed:29281837,
CC PubMed:28801232). Mice infected with an enteric pathogen, such as
CC Citrobacter rodentium, show impaired clearance of the bacteria from
CC colon (PubMed:24581500). Their intestinal epithelium lack a thick
CC continuous overlaying inner mucus layer and exhibit a marked goblet
CC cell hyperplasia along with abrogated mucus secretion
CC (PubMed:24581500). When injected intraperitoneally or intravenously,
CC knockout mice show increased resistance to Salmonella typhimurium,
CC Listeria monocytogenes or Escherichia coli (PubMed:22763455). Mice show
CC reduced intestinal antiviral innate immunity and are more susceptible
CC to oral infection with encephalomyocarditis virus (PubMed:26494172).
CC After crushing the sciatic nerve, mutant mice have a more dramatic drop
CC in sciatic function index immediately upon surgery compared to the
CC control group and need more time to recover fully (PubMed:26253422).
CC Mutant animals show reduced systolic blood pressure without affecting
CC heart rate (PubMed:20923861). Males, but not females, exhibit increased
CC urine flow and decreased ability to reduce urinary flow under water
CC restriction conditions compared to wild type littermates
CC (PubMed:20923861). Mutant males may show somewhat lowered cognitive
CC performance (PubMed:20923861). {ECO:0000269|PubMed:20923861,
CC ECO:0000269|PubMed:21543645, ECO:0000269|PubMed:21565393,
CC ECO:0000269|PubMed:21593405, ECO:0000269|PubMed:22763455,
CC ECO:0000269|PubMed:24581500, ECO:0000269|PubMed:26253422,
CC ECO:0000269|PubMed:26494172, ECO:0000269|PubMed:26638072,
CC ECO:0000269|PubMed:28801232, ECO:0000269|PubMed:29281815,
CC ECO:0000269|PubMed:29281837}.
CC -!- MISCELLANEOUS: [Isoform 2]: Produced by alternative promoter usage.
CC {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 3]: Produced by alternative splicing.
CC {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the NLRP family. {ECO:0000305}.
CC -!- CAUTION: The role of the NLRP6 inflammasome in the regulation of the
CC gut microbiota composition is unclear (PubMed:21565393,
CC PubMed:22763455, PubMed:26638072, PubMed:29281815, PubMed:29281837,
CC PubMed:28801232). Some studies suggest that NLRP6 shapes the commensal
CC gut microbiota composition (PubMed:21565393, PubMed:22763455,
CC PubMed:26638072). However, other groups do not observe any difference
CC in microbiota composition between wild-type and knockout mice
CC (PubMed:29281815, PubMed:29281837, PubMed:28801232). Differences
CC observed were attributed to mother and cage covariates rather than
CC Nlrp6 deficiency (PubMed:29281815, PubMed:29281837, PubMed:28801232).
CC {ECO:0000269|PubMed:21565393, ECO:0000269|PubMed:22763455,
CC ECO:0000269|PubMed:26638072, ECO:0000269|PubMed:28801232,
CC ECO:0000269|PubMed:29281815, ECO:0000269|PubMed:29281837}.
CC -!- SEQUENCE CAUTION:
CC Sequence=ACN32212.1; Type=Frameshift; Evidence={ECO:0000305};
CC ---------------------------------------------------------------------------
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DR EMBL; JF810536; AEI54131.1; -; mRNA.
DR EMBL; AC107815; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC162287; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC013519; AAH13519.1; -; mRNA.
DR EMBL; BC031139; AAH31139.1; -; mRNA.
DR EMBL; FJ222825; ACN32212.1; ALT_FRAME; mRNA.
DR EMBL; AY355343; AAR14740.1; -; mRNA.
DR CCDS; CCDS40178.2; -. [Q91WS2-1]
DR RefSeq; NP_598707.2; NM_133946.2. [Q91WS2-1]
DR RefSeq; XP_006536212.1; XM_006536149.3. [Q91WS2-3]
DR AlphaFoldDB; Q91WS2; -.
DR SMR; Q91WS2; -.
DR DIP; DIP-61874N; -.
DR IntAct; Q91WS2; 3.
DR STRING; 10090.ENSMUSP00000139170; -.
DR PhosphoSitePlus; Q91WS2; -.
DR EPD; Q91WS2; -.
DR MaxQB; Q91WS2; -.
DR PaxDb; Q91WS2; -.
DR PeptideAtlas; Q91WS2; -.
DR PRIDE; Q91WS2; -.
DR ProteomicsDB; 253083; -. [Q91WS2-1]
DR ProteomicsDB; 253084; -. [Q91WS2-2]
DR ProteomicsDB; 253085; -. [Q91WS2-3]
DR Antibodypedia; 58845; 238 antibodies from 29 providers.
DR DNASU; 101613; -.
DR Ensembl; ENSMUST00000183845; ENSMUSP00000139357; ENSMUSG00000038745. [Q91WS2-1]
DR Ensembl; ENSMUST00000184560; ENSMUSP00000139170; ENSMUSG00000038745. [Q91WS2-3]
DR GeneID; 101613; -.
DR KEGG; mmu:101613; -.
DR UCSC; uc009kiv.3; mouse. [Q91WS2-1]
DR UCSC; uc029wpm.2; mouse.
DR CTD; 171389; -.
DR MGI; MGI:2141990; Nlrp6.
DR VEuPathDB; HostDB:ENSMUSG00000038745; -.
DR eggNOG; ENOG502SANB; Eukaryota.
DR GeneTree; ENSGT00940000162758; -.
DR HOGENOM; CLU_002274_2_2_1; -.
DR InParanoid; Q91WS2; -.
DR OMA; QCRVQKL; -.
DR OrthoDB; 114368at2759; -.
DR PhylomeDB; Q91WS2; -.
DR BioGRID-ORCS; 101613; 2 hits in 73 CRISPR screens.
DR PRO; PR:Q91WS2; -.
DR Proteomes; UP000000589; Chromosome 7.
DR RNAct; Q91WS2; protein.
DR Bgee; ENSMUSG00000038745; Expressed in small intestine Peyer's patch and 49 other tissues.
DR ExpressionAtlas; Q91WS2; baseline and differential.
DR Genevisible; Q91WS2; MM.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0061702; C:inflammasome complex; IDA:MGI.
DR GO; GO:0140738; C:NLRP6 inflammasome complex; IDA:UniProtKB.
DR GO; GO:0043228; C:non-membrane-bounded organelle; IDA:UniProtKB.
DR GO; GO:0031965; C:nuclear membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0003725; F:double-stranded RNA binding; IDA:UniProtKB.
DR GO; GO:0001530; F:lipopolysaccharide binding; ISS:UniProtKB.
DR GO; GO:0070891; F:lipoteichoic acid binding; IDA:UniProtKB.
DR GO; GO:0140693; F:molecular condensate scaffold activity; IDA:UniProtKB.
DR GO; GO:0038187; F:pattern recognition receptor activity; IDA:UniProtKB.
DR GO; GO:0042277; F:peptide binding; ISO:MGI.
DR GO; GO:0005000; F:vasopressin receptor activity; ISS:UniProtKB.
DR GO; GO:0097202; P:activation of cysteine-type endopeptidase activity; IMP:MGI.
DR GO; GO:0002526; P:acute inflammatory response; IMP:MGI.
DR GO; GO:0002438; P:acute inflammatory response to antigenic stimulus; IMP:MGI.
DR GO; GO:0140374; P:antiviral innate immune response; IDA:UniProtKB.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IDA:UniProtKB.
DR GO; GO:0051607; P:defense response to virus; IMP:UniProtKB.
DR GO; GO:0048874; P:host-mediated regulation of intestinal microbiota composition; IMP:UniProtKB.
DR GO; GO:0070266; P:necroptotic process; IMP:MGI.
DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; IMP:CACAO.
DR GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB signaling; IMP:CACAO.
DR GO; GO:0050777; P:negative regulation of immune response; IMP:MGI.
DR GO; GO:0002862; P:negative regulation of inflammatory response to antigenic stimulus; IMP:CACAO.
DR GO; GO:0032689; P:negative regulation of interferon-gamma production; IMP:MGI.
DR GO; GO:0043409; P:negative regulation of MAPK cascade; IMP:MGI.
DR GO; GO:0034122; P:negative regulation of toll-like receptor signaling pathway; IMP:MGI.
DR GO; GO:0070946; P:neutrophil-mediated killing of gram-positive bacterium; IMP:MGI.
DR GO; GO:0140739; P:NLRP6 inflammasome complex assembly; IDA:UniProtKB.
DR GO; GO:0050729; P:positive regulation of inflammatory response; IDA:UniProtKB.
DR GO; GO:2000494; P:positive regulation of interleukin-18-mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:0051260; P:protein homooligomerization; IDA:UniProtKB.
DR GO; GO:0070269; P:pyroptosis; IDA:UniProtKB.
DR GO; GO:0010506; P:regulation of autophagy; IMP:MGI.
DR GO; GO:0050727; P:regulation of inflammatory response; IMP:UniProtKB.
DR GO; GO:0070255; P:regulation of mucus secretion; IMP:MGI.
DR GO; GO:0009617; P:response to bacterium; IMP:MGI.
DR GO; GO:0042060; P:wound healing; IMP:MGI.
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; IPR032675; LRR_dom_sf.
DR InterPro; IPR007111; NACHT_NTPase.
DR InterPro; IPR041267; NLRP_HD2.
DR InterPro; IPR041075; NOD2_WH.
DR InterPro; IPR027417; P-loop_NTPase.
DR Pfam; PF05729; NACHT; 1.
DR Pfam; PF17776; NLRC4_HD2; 1.
DR Pfam; PF17779; NOD2_WH; 1.
DR Pfam; PF02758; PYRIN; 1.
DR SMART; SM01289; PYRIN; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR PROSITE; PS50824; DAPIN; 1.
DR PROSITE; PS50837; NACHT; 1.
PE 1: Evidence at protein level;
KW Alternative promoter usage; Alternative splicing; ATP-binding;
KW Cell membrane; Cytoplasm; Immunity; Inflammasome; Inflammatory response;
KW Innate immunity; Leucine-rich repeat; Membrane; Nucleotide-binding;
KW Nucleus; Reference proteome; Repeat; Ubl conjugation.
FT CHAIN 1..869
FT /note="NACHT, LRR and PYD domains-containing protein 6"
FT /id="PRO_0000080893"
FT DOMAIN 37..128
FT /note="Pyrin"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00061"
FT DOMAIN 194..511
FT /note="NACHT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00136"
FT REPEAT 460..485
FT /note="LRR 1"
FT /evidence="ECO:0000255"
FT REPEAT 635..658
FT /note="LRR 2"
FT /evidence="ECO:0000255"
FT REPEAT 837..860
FT /note="LRR 3"
FT /evidence="ECO:0000255"
FT REGION 350..354
FT /note="Disordered"
FT /evidence="ECO:0000269|PubMed:34678144"
FT REGION 577..608
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 200..207
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00136"
FT VAR_SEQ 1..423
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.5"
FT /id="VSP_042301"
FT VAR_SEQ 1..9
FT /note="MDAAGASCS -> MYCPGAPCGECAMCDPGCFGGSGTGPIQVASVMITLLIP
FT (in isoform 3)"
FT /id="VSP_057971"
FT MUTAGEN 170..173
FT /note="RARR->AAAA: Does not affect formation of liquid-
FT liquid phase separation (LLPS)."
FT /evidence="ECO:0000269|PubMed:34678144"
FT MUTAGEN 350..354
FT /note="KDKKK->ADAAA: Impaired formation of liquid-liquid
FT phase separation (LLPS), leading to reduced formation of
FT the NLRP6 inflammasome and GSDMD-dependent release of
FT IL18."
FT /evidence="ECO:0000269|PubMed:34678144"
FT CONFLICT 429
FT /note="G -> F (in Ref. 1; ACN32212)"
FT /evidence="ECO:0000305"
FT CONFLICT 454
FT /note="Missing (in Ref. 1; ACN32212)"
FT /evidence="ECO:0000305"
FT CONFLICT 733
FT /note="P -> R (in Ref. 1; ACN32212)"
FT /evidence="ECO:0000305"
FT CONFLICT 869
FT /note="K -> KIRHTSPASEG (in Ref. 1; ACN32212)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 869 AA; 97402 MW; 801498F67872969F CRC64;
MDAAGASCSS VDAVARELLM ATLEELSQEQ LKRFRHKLRD APLDGRSIPW GRLERSDAVD
LVDKLIEFYE PVPAVEMTRQ VLKRSDIRDV ASRLKQQQLQ KLGPTSVLLS VSAFKKKYRE
HVLRQHAKVK ERNARSVKIN KRFTKLLIAP GTGAVEDELL GPLGEPEPER ARRSDTHTFN
RLFRGNDEES SQPLTVVLQG PAGIGKTMAA KKILYDWAAG KLYHSQVDFA FFMPCGELLE
RPGKRSLADL VLDQCPDRAW PVKRILAQPN RLLFILDGAD ELPTLPSSEA TPCKDPLEAT
SGLRVLSGLL SQELLPGARL LVTTRHAATG RLQGRLCSPQ CAEIRGFSDK DKKKYFFKFF
RDERKAERAY RFVKENETLF ALCFVPFVCW IVCTVLQQQL ELGRDLSRTS KTTTSVYLLF
ITSMLKSAGT NGPRVQGELR TLCRLAREGI LDHHKAQFSE EDLEKLKLRG SQVQTIFLNK
KEIPGVLKTE VTYQFIDQSF QEFLAALSYL LEAERTPGTP AGGVQKLLNS DAELRGHLAL
TTRFLFGLLN TEGLRDIGNH FGCVVPDHVK KDTLRWVQGQ SHPKGPPVGA KKTAELEDIE
DAEEEEEEEE DLNFGLELLY CLYETQEEDF VRQALSSLPE IVLERVRLTR MDLEVLNYCV
QCCPDGQALR LVSCGLVAAK EKKKKKKSLV KRLKGSQSTK KQPPVSLLRP LCETMTTPKC
HLSVLILSHC RLPDAVCRDL SEALKVAPAL RELGLLQSRL TNTGLRLLCE GLAWPKCQVK
TLRMQLPDLQ EVINYLVIVL QQSPVLTTLD LSGCQLPGVI VEPLCAALKH PKCSLKTLSL
TSVELSENSL RDLQAVKTSK PDLSIIYSK
