CASP4_HUMAN
ID CASP4_HUMAN Reviewed; 377 AA.
AC P49662; A2NHL8; A2NHL9; A2NHM0; B3KPZ9; B4DJH5; B4E2D2; O95601; Q7KYX7;
AC Q9UG96;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1996, sequence version 1.
DT 03-AUG-2022, entry version 206.
DE RecName: Full=Caspase-4 {ECO:0000303|PubMed:15123740};
DE Short=CASP-4 {ECO:0000303|PubMed:15123740};
DE EC=3.4.22.57 {ECO:0000269|PubMed:23516580, ECO:0000269|PubMed:7797510};
DE AltName: Full=ICE and Ced-3 homolog 2 {ECO:0000303|PubMed:7797510};
DE Short=ICH-2 {ECO:0000303|PubMed:7797510};
DE AltName: Full=ICE(rel)-II {ECO:0000303|PubMed:7797592};
DE AltName: Full=Mih1 {ECO:0000303|Ref.4};
DE AltName: Full=Protease TX {ECO:0000303|PubMed:7743998};
DE Contains:
DE RecName: Full=Caspase-4 subunit p10;
DE Contains:
DE RecName: Full=Caspase-4 subunit p20;
DE Flags: Precursor;
GN Name=CASP4 {ECO:0000303|PubMed:15123740, ECO:0000312|HGNC:HGNC:1505};
GN Synonyms=ICH2 {ECO:0000303|PubMed:7797510};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, MUTAGENESIS OF CYS-258,
RP 3D-STRUCTURE MODELING, AUTOCATALYSIS, AND TISSUE SPECIFICITY.
RC TISSUE=Placenta;
RX PubMed=7743998; DOI=10.1002/j.1460-2075.1995.tb07183.x;
RA Faucheu C., Diu A., Chan A.W.E., Blanchet A.-M., Miossec C., Herve F.,
RA Collard-Dutilleul V., Gu Y., Aldape R.A., Lippke J.A., Rocher C.,
RA Su M.S.-S., Livingston D.J., Hercend T., Lalanne J.-L.;
RT "A novel human protease similar to the interleukin-1 beta converting enzyme
RT induces apoptosis in transfected cells.";
RL EMBO J. 14:1914-1922(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND TISSUE SPECIFICITY.
RC TISSUE=Monocytic leukemia;
RX PubMed=7797592; DOI=10.1074/jbc.270.26.15870;
RA Munday N.A., Vaillancourt J.P., Ali A., Casano F.J., Miller D.K.,
RA Molineaux S.M., Yamin T.-T., Yu V.L., Nicholson D.W.;
RT "Molecular cloning and pro-apoptotic activity of ICErelII and ICErelIII,
RT members of the ICE/CED-3 family of cysteine proteases.";
RL J. Biol. Chem. 270:15870-15876(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, CATALYTIC ACTIVITY,
RP TISSUE SPECIFICITY, AUTOCATALYTIC CLEAVAGE AT ASP-289, AND
RP BIOPHYSICOCHEMICAL PROPERTIES.
RC TISSUE=Thymus;
RX PubMed=7797510; DOI=10.1074/jbc.270.25.15250;
RA Kamens J., Paskind M., Hugunin M., Talanian R.V., Allen H., Banach D.,
RA Bump N.J., Hackett M.C., Johnston C.G., Li P., Mankovich J.A.,
RA Terranova M., Ghayur T.;
RT "Identification and characterization of ICH-2, a novel member of the
RT interleukin-1 beta-converting enzyme family of cysteine proteases.";
RL J. Biol. Chem. 270:15250-15256(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3).
RC TISSUE=T-cell;
RA Fernandes-Alnemri T., Litwack G., Alnemri E.S.;
RT "Cloning of human ICE homolog Mih1.";
RL Submitted (JUN-1995) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 4 AND 5), AND VARIANT
RP CYS-134.
RC TISSUE=Small intestine, and Trachea;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (MAY-2007) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Testis;
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 [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 161-263 (ISOFORM 4).
RC TISSUE=Uterus;
RX PubMed=11230166; DOI=10.1101/gr.gr1547r;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H., Lauber J.,
RA Duesterhoeft A., Beyer A., Koehrer K., Strack N., Mewes H.-W.,
RA Ottenwaelder B., Obermaier B., Tampe J., Heubner D., Wambutt R., Korn B.,
RA Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and analysis of
RT 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [11]
RP TISSUE SPECIFICITY.
RX PubMed=10986288; DOI=10.1074/jbc.m007255200;
RA Lin X.Y., Choi M.S., Porter A.G.;
RT "Expression analysis of the human caspase-1 subfamily reveals specific
RT regulation of the CASP5 gene by lipopolysaccharide and interferon-gamma.";
RL J. Biol. Chem. 275:39920-39926(2000).
RN [12]
RP FUNCTION, SUBCELLULAR LOCATION, AND CLEAVAGE IN RESPONSE TO ENDOPLASMIC
RP RETICULUM STRESS.
RX PubMed=15123740; DOI=10.1083/jcb.200310015;
RA Hitomi J., Katayama T., Eguchi Y., Kudo T., Taniguchi M., Koyama Y.,
RA Manabe T., Yamagishi S., Bando Y., Imaizumi K., Tsujimoto Y., Tohyama M.;
RT "Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis
RT and Abeta-induced cell death.";
RL J. Cell Biol. 165:347-356(2004).
RN [13]
RP FUNCTION.
RX PubMed=15326478; DOI=10.1038/sj.onc.1208036;
RA Gaggero A., De Ambrosis A., Mezzanzanica D., Piazza T., Rubartelli A.,
RA Figini M., Canevari S., Ferrini S.;
RT "A novel isoform of pro-interleukin-18 expressed in ovarian tumors is
RT resistant to caspase-1 and -4 processing.";
RL Oncogene 23:7552-7560(2004).
RN [14]
RP INDUCTION BY LPS.
RX PubMed=16893518; DOI=10.1016/j.bbrc.2006.07.104;
RA Eckhart L., Kittel C., Gawlas S., Gruber F., Mildner M., Jilma B.,
RA Tschachler E.;
RT "Identification of a novel exon encoding the amino-terminus of the
RT predominant caspase-5 variants.";
RL Biochem. Biophys. Res. Commun. 348:682-688(2006).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [16]
RP INTERACTION WITH NOD2.
RX PubMed=18511561; DOI=10.1073/pnas.0802726105;
RA Hsu L.C., Ali S.R., McGillivray S., Tseng P.H., Mariathasan S., Humke E.W.,
RA Eckmann L., Powell J.J., Nizet V., Dixit V.M., Karin M.;
RT "A NOD2-NALP1 complex mediates caspase-1-dependent IL-1beta secretion in
RT response to Bacillus anthracis infection and muramyl dipeptide.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:7803-7808(2008).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-83, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [18]
RP FUNCTION, INTERACTION WITH CASP1, SUBCELLULAR LOCATION, TISSUE SPECIFICITY,
RP AND MUTAGENESIS OF CYS-258.
RX PubMed=22246630; DOI=10.4049/jimmunol.1101620;
RA Sollberger G., Strittmatter G.E., Kistowska M., French L.E., Beer H.D.;
RT "Caspase-4 is required for activation of inflammasomes.";
RL J. Immunol. 188:1992-2000(2012).
RN [19]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2 (ISOFORM 2), CLEAVAGE OF
RP INITIATOR METHIONINE [LARGE SCALE ANALYSIS] (ISOFORM 2), AND IDENTIFICATION
RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [20]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH TMEM214, AND MUTAGENESIS
RP OF CYS-258.
RX PubMed=23661706; DOI=10.1074/jbc.m113.458836;
RA Li C., Wei J., Li Y., He X., Zhou Q., Yan J., Zhang J., Liu Y., Liu Y.,
RA Shu H.B.;
RT "Transmembrane protein 214 (TMEM214) mediates endoplasmic reticulum stress-
RT induced caspase 4 enzyme activation and apoptosis.";
RL J. Biol. Chem. 288:17908-17917(2013).
RN [21]
RP INTERACTION WITH E.COLI NLEF (MICROBIAL INFECTION), CATALYTIC ACTIVITY,
RP FUNCTION, AND ACTIVITY REGULATION (MICROBIAL INFECTION).
RX PubMed=23516580; DOI=10.1371/journal.pone.0058937;
RA Blasche S., Mortl M., Steuber H., Siszler G., Nisa S., Schwarz F.,
RA Lavrik I., Gronewold T.M., Maskos K., Donnenberg M.S., Ullmann D., Uetz P.,
RA Kogl M.;
RT "The E. coli effector protein NleF is a caspase inhibitor.";
RL PLoS ONE 8:E58937-E58937(2013).
RN [22]
RP FUNCTION, TISSUE SPECIFICITY, AND INDUCTION BY LPS.
RX PubMed=25121752; DOI=10.1016/j.chom.2014.07.002;
RA Knodler L.A., Crowley S.M., Sham H.P., Yang H., Wrande M., Ma C.,
RA Ernst R.K., Steele-Mortimer O., Celli J., Vallance B.A.;
RT "Noncanonical inflammasome activation of caspase-4/caspase-11 mediates
RT epithelial defenses against enteric bacterial pathogens.";
RL Cell Host Microbe 16:249-256(2014).
RN [23]
RP FUNCTION, AND INDUCTION BY LPS.
RX PubMed=24879791; DOI=10.4049/jimmunol.1303424;
RA Kajiwara Y., Schiff T., Voloudakis G., Gama Sosa M.A., Elder G.,
RA Bozdagi O., Buxbaum J.D.;
RT "A critical role for human caspase-4 in endotoxin sensitivity.";
RL J. Immunol. 193:335-343(2014).
RN [24]
RP FUNCTION, OLIGOMERIZATION, INTERACTION WITH LPS, ACTIVITY REGULATION,
RP SUBCELLULAR LOCATION, DOMAIN, AND MUTAGENESIS OF CYS-258.
RX PubMed=25119034; DOI=10.1038/nature13683;
RA Shi J., Zhao Y., Wang Y., Gao W., Ding J., Li P., Hu L., Shao F.;
RT "Inflammatory caspases are innate immune receptors for intracellular LPS.";
RL Nature 514:187-192(2014).
RN [25]
RP FUNCTION.
RX PubMed=26174085; DOI=10.1002/eji.201545523;
RA Schmid-Burgk J.L., Gaidt M.M., Schmidt T., Ebert T.S., Bartok E.,
RA Hornung V.;
RT "Caspase-4 mediates non-canonical activation of the NLRP3 inflammasome in
RT human myeloid cells.";
RL Eur. J. Immunol. 45:2911-2917(2015).
RN [26]
RP FUNCTION.
RX PubMed=26173988; DOI=10.1002/eji.201545655;
RA Baker P.J., Boucher D., Bierschenk D., Tebartz C., Whitney P.G.,
RA D'Silva D.B., Tanzer M.C., Monteleone M., Robertson A.A., Cooper M.A.,
RA Alvarez-Diaz S., Herold M.J., Bedoui S., Schroder K., Masters S.L.;
RT "NLRP3 inflammasome activation downstream of cytoplasmic LPS recognition by
RT both caspase-4 and caspase-5.";
RL Eur. J. Immunol. 45:2918-2926(2015).
RN [27]
RP FUNCTION, AND INDUCTION BY LPS.
RX PubMed=26508369; DOI=10.1038/ncomms9761;
RA Vigano E., Diamond C.E., Spreafico R., Balachander A., Sobota R.M.,
RA Mortellaro A.;
RT "Human caspase-4 and caspase-5 regulate the one-step non-canonical
RT inflammasome activation in monocytes.";
RL Nat. Commun. 6:8761-8761(2015).
RN [28]
RP FUNCTION, AND GSDMD CLEAVAGE.
RX PubMed=26375003; DOI=10.1038/nature15514;
RA Shi J., Zhao Y., Wang K., Shi X., Wang Y., Huang H., Zhuang Y., Cai T.,
RA Wang F., Shao F.;
RT "Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell
RT death.";
RL Nature 526:660-665(2015).
RN [29]
RP INDUCTION BY NF-KAPPA-B.
RX PubMed=25695505; DOI=10.1371/journal.pone.0117953;
RA Yang H.J., Wang M., Wang L., Cheng B.F., Lin X.Y., Feng Z.W.;
RT "NF-kappaB regulates caspase-4 expression and sensitizes neuroblastoma
RT cells to Fas-induced apoptosis.";
RL PLoS ONE 10:E0117953-E0117953(2015).
RN [30]
RP FUNCTION, AND INDUCTION BY LPS AND IFNB1.
RX PubMed=25964352; DOI=10.1073/pnas.1421699112;
RA Casson C.N., Yu J., Reyes V.M., Taschuk F.O., Yadav A., Copenhaver A.M.,
RA Nguyen H.T., Collman R.G., Shin S.;
RT "Human caspase-4 mediates noncanonical inflammasome activation against
RT gram-negative bacterial pathogens.";
RL Proc. Natl. Acad. Sci. U.S.A. 112:6688-6693(2015).
RN [31]
RP FUNCTION, AND MUTAGENESIS OF CYS-258.
RX PubMed=28314590; DOI=10.1016/j.immuni.2017.02.011;
RA Wang Y., Ning X., Gao P., Wu S., Sha M., Lv M., Zhou X., Gao J., Fang R.,
RA Meng G., Su X., Jiang Z.;
RT "Inflammasome activation triggers caspase-1-mediated cleavage of cGAS to
RT regulate responses to DNA virus infection.";
RL Immunity 46:393-404(2017).
RN [32]
RP FUNCTION, AND INTERACTION WITH CTSG.
RX PubMed=29077095; DOI=10.1038/cdd.2017.167;
RA Jun H.K., Jung Y.J., Ji S., An S.J., Choi B.K.;
RT "Caspase-4 activation by a bacterial surface protein is mediated by
RT cathepsin G in human gingival fibroblasts.";
RL Cell Death Differ. 25:380-391(2018).
RN [33]
RP INTERACTION WITH SERPINB1.
RX PubMed=30692621; DOI=10.1038/s41590-018-0303-z;
RA Choi Y.J., Kim S., Choi Y., Nielsen T.B., Yan J., Lu A., Ruan J., Lee H.R.,
RA Wu H., Spellberg B., Jung J.U.;
RT "SERPINB1-mediated checkpoint of inflammatory caspase activation.";
RL Nat. Immunol. 20:276-287(2019).
RN [34]
RP FUNCTION.
RX PubMed=33377178; DOI=10.1111/iej.13469;
RA Tian X.X., Li R., Liu C., Liu F., Yang L.J., Wang S.P., Wang C.L.;
RT "NLRP6-caspase 4 inflammasome activation in response to cariogenic
RT bacterial lipoteichoic acid in human dental pulp inflammation.";
RL Int. Endod. J. 54:916-925(2021).
RN [35]
RP FUNCTION, PROTEOLYTIC CLEAVAGE, ADP-RIBOXANATION AT ARG-314 (MICROBIAL
RP INFECTION), AND MUTAGENESIS OF ARG-314.
RX PubMed=34671164; DOI=10.1038/s41586-021-04020-1;
RA Li Z., Liu W., Fu J., Cheng S., Xu Y., Wang Z., Liu X., Shi X., Liu Y.,
RA Qi X., Liu X., Ding J., Shao F.;
RT "Shigella evades pyroptosis by arginine ADP-riboxanation of caspase-11.";
RL Nature 599:290-295(2021).
RN [36] {ECO:0007744|PDB:6KMZ}
RP X-RAY CRYSTALLOGRAPHY (3.61 ANGSTROMS) OF 105-289 AND 290-377 IN COMPLEX
RP WITH GSDMD, FUNCTION, SUBUNIT, PROTEOLYTIC CLEAVAGE, AND MUTAGENESIS OF
RP TRP-267; ASP-270 AND VAL-291.
RX PubMed=32109412; DOI=10.1016/j.cell.2020.02.002;
RA Wang K., Sun Q., Zhong X., Zeng M., Zeng H., Shi X., Li Z., Wang Y.,
RA Zhao Q., Shao F., Ding J.;
RT "Structural mechanism for GSDMD targeting by autoprocessed caspases in
RT pyroptosis.";
RL Cell 180:941-955(2020).
CC -!- FUNCTION: Inflammatory caspase that acts as an essential effector of
CC the NLRP3 and NLRP6 inflammasomes by mediating lipopolysaccharide
CC (LPS)-induced pyroptosis (PubMed:7797510, PubMed:23516580,
CC PubMed:26375003, PubMed:32109412). Thiol protease that cleaves a
CC tetrapeptide after an Asp residue at position P1: catalyzes cleavage of
CC CGAS, GSDMD and IL18 (PubMed:7797510, PubMed:15326478, PubMed:23516580,
CC PubMed:26375003, PubMed:28314590, PubMed:32109412). Required for innate
CC immunity to cytosolic, but not vacuolar, bacteria (By similarity).
CC Plays a key role in NLRP3-dependent CASP1 activation and IL1B and IL18
CC secretion in response to non-canonical activators, such as UVB
CC radiation, cholera enterotoxin subunit B and cytosolic LPS
CC (PubMed:26508369, PubMed:22246630, PubMed:23516580, PubMed:24879791,
CC PubMed:25119034, PubMed:26173988, PubMed:26174085, PubMed:25964352).
CC Activated by direct binding to LPS without the need of an upstream
CC sensor (PubMed:25119034). Involved in NLRP6 inflammasome-dependent
CC activation in response to lipoteichoic acid (LTA), a cell-wall
CC component of Gram-positive bacteria, which leads to CASP1 activation
CC and IL1B and IL18 secretion (PubMed:33377178). Independently of NLRP3
CC inflammasome and CASP1, promotes pyroptosis, through GSDMD cleavage and
CC activation, followed by IL1A, IL18 and HMGB1 release in response to
CC non-canonical inflammasome activators (PubMed:26375003,
CC PubMed:32109412). Plays a crucial role in the restriction of Salmonella
CC typhimurium replication in colonic epithelial cells during infection:
CC in later stages of the infection, LPS from cytosolic Salmonella
CC triggers CASP4 activation, which catalyzes cleavage of GSDMD, resulting
CC in pyroptosis of infected cells and their extrusion into the gut lumen,
CC as well as in IL18 secretion (PubMed:25121752, PubMed:26375003,
CC PubMed:25964352, PubMed:34671164, PubMed:32109412). Cleavage of GSDMD
CC is not strictly dependent on the consensus cleavage site but depends on
CC an exosite interface on CASP4 that recognizes and binds the Gasdermin-
CC D, C-terminal (GSDMD-CT) part (PubMed:32109412). Pyroptosis limits
CC bacterial replication, while cytokine secretion promotes the
CC recruitment and activation of immune cells and triggers mucosal
CC inflammation (PubMed:25121752, PubMed:26375003, PubMed:25964352).
CC Involved in LPS-induced IL6 secretion; this activity may not require
CC caspase enzymatic activity (PubMed:26508369). Involved in cell death
CC induced by endoplasmic reticulum stress and by treatment with cytotoxic
CC APP peptides found in Alzheimer's patient brains (PubMed:23661706,
CC PubMed:15123740, PubMed:22246630). Catalyzes cleavage and maturation of
CC IL18 (PubMed:15326478). In contrast, it does not directly process IL1B
CC (PubMed:7743998, PubMed:7797592, PubMed:7797510). During non-canonical
CC inflammasome activation, cuts CGAS and may play a role in the
CC regulation of antiviral innate immune activation (PubMed:28314590).
CC {ECO:0000250|UniProtKB:P70343, ECO:0000269|PubMed:15123740,
CC ECO:0000269|PubMed:15326478, ECO:0000269|PubMed:22246630,
CC ECO:0000269|PubMed:23516580, ECO:0000269|PubMed:23661706,
CC ECO:0000269|PubMed:24879791, ECO:0000269|PubMed:25119034,
CC ECO:0000269|PubMed:25121752, ECO:0000269|PubMed:25964352,
CC ECO:0000269|PubMed:26173988, ECO:0000269|PubMed:26174085,
CC ECO:0000269|PubMed:26375003, ECO:0000269|PubMed:26508369,
CC ECO:0000269|PubMed:28314590, ECO:0000269|PubMed:32109412,
CC ECO:0000269|PubMed:33377178, ECO:0000269|PubMed:34671164,
CC ECO:0000269|PubMed:7743998, ECO:0000269|PubMed:7797510,
CC ECO:0000269|PubMed:7797592}.
CC -!- FUNCTION: (Microbial infection) In response to the Td92 surface protein
CC of the periodontal pathogen T.denticola, activated by cathepsin CTSG
CC which leads to production and secretion of IL1A and pyroptosis of
CC gingival fibroblasts. {ECO:0000269|PubMed:29077095}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Strict requirement for Asp at the P1 position. It has a
CC preferred cleavage sequence of Tyr-Val-Ala-Asp-|- but also cleaves at
CC Asp-Glu-Val-Asp-|-.; EC=3.4.22.57;
CC Evidence={ECO:0000269|PubMed:23516580, ECO:0000269|PubMed:7797510};
CC -!- ACTIVITY REGULATION: Activated by homooligomerization induced by direct
CC binding to cytosolic LPS, in a TLR4-independent manner
CC (PubMed:25119034). {ECO:0000269|PubMed:25119034}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=681 uM for synthetic peptide acetyl-YVAD-p-nitroanilide
CC {ECO:0000269|PubMed:7797510};
CC Note=Values obtained using the partial C-terminal enzyme sequence of
CC 105-377. {ECO:0000269|PubMed:7797510};
CC -!- SUBUNIT: Heterotetramer that consists of two anti-parallel arranged
CC heterodimers, each one formed by a 20 kDa (Caspase-4 subunit p20) and a
CC 10 kDa (Caspase-4 subunit p10) subunit (PubMed:32109412). Upon direct
CC LPS-binding, forms large homooligomers, resulting in its activation (By
CC similarity). These oligomers are often referred to as 'non-canonical
CC inflammasomes' (PubMed:25119034). In its precursor form, interacts with
CC TMEM214; this interaction is required for association with the
CC endoplasmic reticulum membrane (PubMed:23661706). Interacts with CASP1
CC (PubMed:22246630). Interacts with NOD2 (PubMed:18511561). Interacts
CC with SERPINB1; this interaction regulates CASP4 activity
CC (PubMed:30692621). {ECO:0000250|UniProtKB:P70343,
CC ECO:0000269|PubMed:18511561, ECO:0000269|PubMed:22246630,
CC ECO:0000269|PubMed:23661706, ECO:0000269|PubMed:25119034,
CC ECO:0000269|PubMed:30692621, ECO:0000269|PubMed:32109412}.
CC -!- SUBUNIT: [Caspase-4 subunit p20]: Heterotetramer that consists of two
CC anti-parallel arranged heterodimers, each one formed by a 20 kDa
CC (Caspase-4 subunit p20) and a 10 kDa (Caspase-4 subunit p10) subunit.
CC {ECO:0000269|PubMed:32109412}.
CC -!- SUBUNIT: [Caspase-4 subunit p10]: Heterotetramer that consists of two
CC anti-parallel arranged heterodimers, each one formed by a 20 kDa
CC (Caspase-4 subunit p20) and a 10 kDa (Caspase-4 subunit p10) subunit.
CC {ECO:0000269|PubMed:32109412}.
CC -!- SUBUNIT: (Microbial infection) Interacts with NleF protein from
CC pathogenic E.coli; this interaction leads to enzyme inhibition.
CC {ECO:0000269|PubMed:23516580}.
CC -!- SUBUNIT: (Microbial infection) Interacts with cathepsin CTSG; the
CC interaction is promoted by the Td92 surface protein of the periodontal
CC pathogen T.denticola and leads to CASP4 activation.
CC {ECO:0000269|PubMed:29077095}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:23661706}.
CC Endoplasmic reticulum membrane {ECO:0000269|PubMed:15123740,
CC ECO:0000269|PubMed:23661706}; Peripheral membrane protein
CC {ECO:0000269|PubMed:23661706}; Cytoplasmic side
CC {ECO:0000269|PubMed:23661706}. Mitochondrion
CC {ECO:0000269|PubMed:15123740, ECO:0000269|PubMed:23661706}.
CC Inflammasome {ECO:0000269|PubMed:25119034,
CC ECO:0000269|PubMed:26508369}. Secreted {ECO:0000269|PubMed:22246630}.
CC Note=Predominantly localizes to the endoplasmic reticulum (ER).
CC Association with the ER membrane requires TMEM214 (PubMed:15123740).
CC Released in the extracellular milieu by keratinocytes following UVB
CC irradiation (PubMed:22246630). {ECO:0000269|PubMed:15123740,
CC ECO:0000269|PubMed:22246630}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1; Synonyms=Alpha;
CC IsoId=P49662-1; Sequence=Displayed;
CC Name=2; Synonyms=Gamma, mih1-beta;
CC IsoId=P49662-2; Sequence=VSP_043495;
CC Name=3; Synonyms=mih1-delta;
CC IsoId=P49662-3; Sequence=VSP_058177, VSP_058178;
CC Name=4;
CC IsoId=P49662-4; Sequence=VSP_058181, VSP_058182;
CC Name=5;
CC IsoId=P49662-5; Sequence=VSP_058179, VSP_058180;
CC -!- TISSUE SPECIFICITY: Widely expressed, including in keratinocytes and
CC colonic and small intestinal epithelial cells (at protein level). Not
CC detected in brain. {ECO:0000269|PubMed:10986288,
CC ECO:0000269|PubMed:22246630, ECO:0000269|PubMed:25121752,
CC ECO:0000269|PubMed:7743998, ECO:0000269|PubMed:7797510,
CC ECO:0000269|PubMed:7797592}.
CC -!- INDUCTION: In peripheral blood mononuclear cells and purified
CC monocytes, up-regulated by bacterial lipopolysaccharides (LPS) and
CC interferon-beta/IFNB1 at the mRNA level (PubMed:16893518,
CC PubMed:24879791). However, this increase is not observed at the protein
CC level, which remains constant in monocytes and other cell types
CC following LPS treatment (PubMed:25121752) (PubMed:26508369). In
CC monocyte-derived macrophages, some up-regulation at the protein level
CC is observed following treatment with LPS and IFNB1 (PubMed:25964352).
CC In SH-EP1 neuroblastoma cell line, up-regulated by NF-kappa-B RELA/p65
CC at both mRNA and protein levels. {ECO:0000269|PubMed:16893518,
CC ECO:0000269|PubMed:24879791, ECO:0000269|PubMed:25695505}.
CC -!- DOMAIN: The CARD domain mediates LPS recognition and
CC homooligomerization. {ECO:0000269|PubMed:25119034}.
CC -!- PTM: In response to activation signals, including endoplasmic reticulum
CC stress or treatment with amyloid-beta A4 protein fragments (such as
CC amyloid-beta protein 40), undergoes autoproteolytic cleavage.
CC {ECO:0000269|PubMed:15123740, ECO:0000269|PubMed:32109412,
CC ECO:0000269|PubMed:34671164, ECO:0000269|PubMed:7743998,
CC ECO:0000269|PubMed:7797510}.
CC -!- PTM: (Microbial infection) ADP-riboxanation by S.flexneri OspC3 blocks
CC CASP4 autoprocessing, preventing CASP4 activation and ability to
CC recognize and cleave GSDMD, thereby thwarting the
CC inflammasome/pyroptosis-mediated defense.
CC {ECO:0000269|PubMed:34671164}.
CC -!- MISCELLANEOUS: [Isoform 3]: May be due to competing acceptor splice
CC site. May be produced at very low levels due to a premature stop codon
CC in the mRNA, leading to nonsense-mediated mRNA decay. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the peptidase C14A family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC99854.1; Type=Erroneous translation; Note=Erroneous CDS prediction.; Evidence={ECO:0000305};
CC Sequence=EAW67050.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
CC -!- SEQUENCE CAUTION: [Isoform 2]:
CC Sequence=AAC99851.1; Type=Frameshift; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/casp4/";
CC ---------------------------------------------------------------------------
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DR EMBL; Z48810; CAA88750.1; -; mRNA.
DR EMBL; U28014; AAA75171.1; -; mRNA.
DR EMBL; U25804; AAA86890.1; -; mRNA.
DR EMBL; U28976; AAC99850.1; -; mRNA.
DR EMBL; U28977; AAC99851.1; ALT_FRAME; mRNA.
DR EMBL; U28978; AAC99852.1; -; mRNA.
DR EMBL; U28979; AAC99853.1; -; mRNA.
DR EMBL; U28979; AAC99854.1; ALT_SEQ; mRNA.
DR EMBL; AK057094; BAG51861.1; -; mRNA.
DR EMBL; AK296081; BAG58837.1; -; mRNA.
DR EMBL; AK304222; BAG65094.1; -; mRNA.
DR EMBL; EF636667; ABR09278.1; -; Genomic_DNA.
DR EMBL; AP001153; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP002004; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471065; EAW67050.1; ALT_SEQ; Genomic_DNA.
DR EMBL; CH471065; EAW67051.1; -; Genomic_DNA.
DR EMBL; CH471065; EAW67052.1; -; Genomic_DNA.
DR EMBL; BC017839; AAH17839.1; -; mRNA.
DR EMBL; AL050391; CAB43686.2; -; mRNA.
DR CCDS; CCDS41704.1; -. [P49662-2]
DR CCDS; CCDS8327.1; -. [P49662-1]
DR PIR; A57511; A57511.
DR RefSeq; NP_001216.1; NM_001225.3. [P49662-1]
DR RefSeq; NP_150649.1; NM_033306.2. [P49662-2]
DR RefSeq; XP_011541321.1; XM_011543019.1.
DR RefSeq; XP_016873886.1; XM_017018397.1.
DR PDB; 6KMZ; X-ray; 3.61 A; A/B/C/D=105-377.
DR PDB; 6NRY; X-ray; 2.18 A; A=92-377.
DR PDBsum; 6KMZ; -.
DR PDBsum; 6NRY; -.
DR AlphaFoldDB; P49662; -.
DR SMR; P49662; -.
DR BioGRID; 107287; 38.
DR DIP; DIP-44806N; -.
DR IntAct; P49662; 7.
DR MINT; P49662; -.
DR STRING; 9606.ENSP00000388566; -.
DR BindingDB; P49662; -.
DR ChEMBL; CHEMBL2226; -.
DR DrugBank; DB06255; Incadronic acid.
DR GuidetoPHARMACOLOGY; 1620; -.
DR MEROPS; C14.007; -.
DR iPTMnet; P49662; -.
DR MetOSite; P49662; -.
DR PhosphoSitePlus; P49662; -.
DR BioMuta; CASP4; -.
DR DMDM; 1352420; -.
DR EPD; P49662; -.
DR jPOST; P49662; -.
DR MassIVE; P49662; -.
DR MaxQB; P49662; -.
DR PaxDb; P49662; -.
DR PeptideAtlas; P49662; -.
DR PRIDE; P49662; -.
DR ProteomicsDB; 56043; -. [P49662-1]
DR ProteomicsDB; 56044; -. [P49662-2]
DR Antibodypedia; 18094; 756 antibodies from 43 providers.
DR DNASU; 837; -.
DR Ensembl; ENST00000393150.7; ENSP00000376857.3; ENSG00000196954.14. [P49662-2]
DR Ensembl; ENST00000444739.7; ENSP00000388566.2; ENSG00000196954.14. [P49662-1]
DR GeneID; 837; -.
DR KEGG; hsa:837; -.
DR MANE-Select; ENST00000444739.7; ENSP00000388566.2; NM_001225.4; NP_001216.1.
DR UCSC; uc001pib.2; human. [P49662-1]
DR CTD; 837; -.
DR DisGeNET; 837; -.
DR GeneCards; CASP4; -.
DR HGNC; HGNC:1505; CASP4.
DR HPA; ENSG00000196954; Low tissue specificity.
DR MIM; 602664; gene.
DR neXtProt; NX_P49662; -.
DR OpenTargets; ENSG00000196954; -.
DR PharmGKB; PA26088; -.
DR VEuPathDB; HostDB:ENSG00000196954; -.
DR eggNOG; KOG3573; Eukaryota.
DR GeneTree; ENSGT00940000161497; -.
DR HOGENOM; CLU_036904_0_1_1; -.
DR InParanoid; P49662; -.
DR OMA; WKMKMDD; -.
DR OrthoDB; 1327703at2759; -.
DR PhylomeDB; P49662; -.
DR TreeFam; TF102023; -.
DR BRENDA; 3.4.22.57; 2681.
DR PathwayCommons; P49662; -.
DR Reactome; R-HSA-168638; NOD1/2 Signaling Pathway.
DR Reactome; R-HSA-5620971; Pyroptosis.
DR SABIO-RK; P49662; -.
DR SignaLink; P49662; -.
DR SIGNOR; P49662; -.
DR BioGRID-ORCS; 837; 13 hits in 1077 CRISPR screens.
DR ChiTaRS; CASP4; human.
DR GenomeRNAi; 837; -.
DR Pharos; P49662; Tchem.
DR PRO; PR:P49662; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; P49662; protein.
DR Bgee; ENSG00000196954; Expressed in monocyte and 177 other tissues.
DR ExpressionAtlas; P49662; baseline and differential.
DR Genevisible; P49662; HS.
DR GO; GO:0097169; C:AIM2 inflammasome complex; IBA:GO_Central.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0072557; C:IPAF inflammasome complex; IBA:GO_Central.
DR GO; GO:0005739; C:mitochondrion; IDA:ParkinsonsUK-UCL.
DR GO; GO:0072559; C:NLRP3 inflammasome complex; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB.
DR GO; GO:0050700; F:CARD domain binding; IPI:UniProtKB.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0097199; F:cysteine-type endopeptidase activity involved in apoptotic signaling pathway; IBA:GO_Central.
DR GO; GO:0006915; P:apoptotic process; TAS:ProtInc.
DR GO; GO:1904646; P:cellular response to amyloid-beta; IMP:ParkinsonsUK-UCL.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IDA:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; IMP:ParkinsonsUK-UCL.
DR GO; GO:0070059; P:intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; IMP:ParkinsonsUK-UCL.
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:1903265; P:positive regulation of tumor necrosis factor-mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:0016540; P:protein autoprocessing; IDA:UniProtKB.
DR GO; GO:0006508; P:proteolysis; TAS:ProtInc.
DR GO; GO:0070269; P:pyroptosis; IDA:UniProtKB.
DR GO; GO:0042981; P:regulation of apoptotic process; IEA:InterPro.
DR GO; GO:0050727; P:regulation of inflammatory response; IDA:UniProtKB.
DR CDD; cd00032; CASc; 1.
DR Gene3D; 1.10.533.10; -; 1.
DR InterPro; IPR001315; CARD.
DR InterPro; IPR029030; Caspase-like_dom_sf.
DR InterPro; IPR033139; Caspase_cys_AS.
DR InterPro; IPR016129; Caspase_his_AS.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR InterPro; IPR002398; Pept_C14.
DR InterPro; IPR002138; Pept_C14_p10.
DR InterPro; IPR001309; Pept_C14_p20.
DR InterPro; IPR015917; Pept_C14A.
DR PANTHER; PTHR10454; PTHR10454; 1.
DR Pfam; PF00619; CARD; 1.
DR PRINTS; PR00376; IL1BCENZYME.
DR SMART; SM00114; CARD; 1.
DR SMART; SM00115; CASc; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF52129; SSF52129; 1.
DR PROSITE; PS50209; CARD; 1.
DR PROSITE; PS01122; CASPASE_CYS; 1.
DR PROSITE; PS01121; CASPASE_HIS; 1.
DR PROSITE; PS50207; CASPASE_P10; 1.
DR PROSITE; PS50208; CASPASE_P20; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Cytoplasm;
KW Endoplasmic reticulum; Hydrolase; Immunity; Inflammasome;
KW Inflammatory response; Innate immunity; Membrane; Mitochondrion; Necrosis;
KW Phosphoprotein; Protease; Reference proteome; Secreted; Thiol protease;
KW Zymogen.
FT PROPEP 1..?80
FT /evidence="ECO:0000255"
FT /id="PRO_0000004596"
FT CHAIN ?81..270
FT /note="Caspase-4 subunit p20"
FT /evidence="ECO:0000305|PubMed:32109412"
FT /id="PRO_0000004597"
FT PROPEP 271..289
FT /evidence="ECO:0000255, ECO:0000305|PubMed:7797510"
FT /id="PRO_0000004598"
FT CHAIN 290..377
FT /note="Caspase-4 subunit p10"
FT /evidence="ECO:0000305|PubMed:32109412"
FT /id="PRO_0000004599"
FT DOMAIN 1..91
FT /note="CARD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00046"
FT REGION 1..59
FT /note="Required for LPS-binding"
FT /evidence="ECO:0000250|UniProtKB:P70343"
FT REGION 84..104
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 210
FT /evidence="ECO:0000250|UniProtKB:P29466"
FT ACT_SITE 258
FT /evidence="ECO:0000269|PubMed:22246630,
FT ECO:0000269|PubMed:23661706, ECO:0000269|PubMed:25119034,
FT ECO:0000269|PubMed:7743998"
FT SITE 289..290
FT /note="Cleavage; by autolysis"
FT /evidence="ECO:0000269|PubMed:7797510"
FT MOD_RES 83
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:20068231"
FT MOD_RES 314
FT /note="(Microbial infection) ADP-riboxanated arginine"
FT /evidence="ECO:0000269|PubMed:34671164"
FT VAR_SEQ 1..56
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.4"
FT /id="VSP_043495"
FT VAR_SEQ 88..116
FT /note="AHPNMEAGPPESGESTDALKLCPHEEFLR -> GDKLGHRGRNHNLCSAISC
FT SSSEYGGWTT (in isoform 3)"
FT /evidence="ECO:0000303|Ref.4"
FT /id="VSP_058177"
FT VAR_SEQ 117..377
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|Ref.4"
FT /id="VSP_058178"
FT VAR_SEQ 125..157
FT /note="IYPIKERNNRTRLALIICNTEFDHLPPRNGADF -> VLCYLYEIEKKEEIS
FT LLSFSAPFLTALNDWGWG (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_058179"
FT VAR_SEQ 158..377
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_058180"
FT VAR_SEQ 261..263
FT /note="ANR -> GEC (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:11230166,
FT ECO:0000303|PubMed:14702039"
FT /id="VSP_058181"
FT VAR_SEQ 264..377
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:11230166,
FT ECO:0000303|PubMed:14702039"
FT /id="VSP_058182"
FT VARIANT 47
FT /note="D -> N (in dbSNP:rs56226603)"
FT /id="VAR_061081"
FT VARIANT 134
FT /note="R -> C (in dbSNP:rs181090259)"
FT /evidence="ECO:0000269|PubMed:14702039"
FT /id="VAR_075654"
FT VARIANT 284
FT /note="E -> D (in dbSNP:rs55901059)"
FT /id="VAR_061082"
FT MUTAGEN 258
FT /note="C->A: Loss of enzymatic activity. Loss of LPS-
FT induced pyroptosis. No effect on the interaction with LPS.
FT Decrease in cell death induced by TMEM214 overexpression.
FT Does not support IL1B and IL18 secretion following UVB
FT irradiation."
FT /evidence="ECO:0000269|PubMed:22246630,
FT ECO:0000269|PubMed:23661706, ECO:0000269|PubMed:25119034,
FT ECO:0000269|PubMed:28314590"
FT MUTAGEN 258
FT /note="C->S: Loss of autocatalysis."
FT /evidence="ECO:0000269|PubMed:7743998"
FT MUTAGEN 267
FT /note="W->L,N: Abolished interaction with Gasdermin-D
FT (GSDMD) and ability to mediate its cleavage."
FT /evidence="ECO:0000269|PubMed:32109412"
FT MUTAGEN 270
FT /note="D->A: Abolished autoprocessing and ability to form a
FT heterotetramer composed of Caspase-4 subunit p10 and
FT Caspase-4 subunit p20, preventing ability to cleave GSDMD
FT and induce pyroptosis."
FT /evidence="ECO:0000269|PubMed:32109412"
FT MUTAGEN 291
FT /note="V->N: Abolished interaction with Gasdermin-D (GSDMD)
FT and ability to mediate its cleavage."
FT /evidence="ECO:0000269|PubMed:32109412"
FT MUTAGEN 314
FT /note="R->A: Abolished ability to cleave Gasdermin-D
FT (GSDMD)."
FT /evidence="ECO:0000269|PubMed:34671164"
FT HELIX 111..120
FT /evidence="ECO:0007829|PDB:6NRY"
FT HELIX 122..124
FT /evidence="ECO:0007829|PDB:6NRY"
FT TURN 131..133
FT /evidence="ECO:0007829|PDB:6NRY"
FT STRAND 136..142
FT /evidence="ECO:0007829|PDB:6NRY"
FT STRAND 147..149
FT /evidence="ECO:0007829|PDB:6NRY"
FT HELIX 155..168
FT /evidence="ECO:0007829|PDB:6NRY"
FT STRAND 171..178
FT /evidence="ECO:0007829|PDB:6NRY"
FT HELIX 181..192
FT /evidence="ECO:0007829|PDB:6NRY"
FT HELIX 195..197
FT /evidence="ECO:0007829|PDB:6NRY"
FT STRAND 203..212
FT /evidence="ECO:0007829|PDB:6NRY"
FT STRAND 215..217
FT /evidence="ECO:0007829|PDB:6NRY"
FT STRAND 223..225
FT /evidence="ECO:0007829|PDB:6NRY"
FT STRAND 228..230
FT /evidence="ECO:0007829|PDB:6NRY"
FT HELIX 231..237
FT /evidence="ECO:0007829|PDB:6NRY"
FT TURN 240..242
FT /evidence="ECO:0007829|PDB:6NRY"
FT HELIX 244..246
FT /evidence="ECO:0007829|PDB:6NRY"
FT STRAND 251..258
FT /evidence="ECO:0007829|PDB:6NRY"
FT STRAND 295..297
FT /evidence="ECO:0007829|PDB:6NRY"
FT STRAND 299..305
FT /evidence="ECO:0007829|PDB:6NRY"
FT HELIX 313..316
FT /evidence="ECO:0007829|PDB:6NRY"
FT HELIX 321..333
FT /evidence="ECO:0007829|PDB:6NRY"
FT TURN 334..336
FT /evidence="ECO:0007829|PDB:6NRY"
FT HELIX 339..349
FT /evidence="ECO:0007829|PDB:6NRY"
FT TURN 353..355
FT /evidence="ECO:0007829|PDB:6NRY"
FT HELIX 356..358
FT /evidence="ECO:0007829|PDB:6NRY"
FT STRAND 361..364
FT /evidence="ECO:0007829|PDB:6NRY"
FT STRAND 368..370
FT /evidence="ECO:0007829|PDB:6NRY"
FT INIT_MET P49662-2:1
FT /note="Removed"
FT /evidence="ECO:0007744|PubMed:22814378"
FT MOD_RES P49662-2:2
FT /note="N-acetylalanine"
FT /evidence="ECO:0007744|PubMed:22814378"
SQ SEQUENCE 377 AA; 43262 MW; DC7CCEC6E9D483EB CRC64;
MAEGNHRKKP LKVLESLGKD FLTGVLDNLV EQNVLNWKEE EKKKYYDAKT EDKVRVMADS
MQEKQRMAGQ MLLQTFFNID QISPNKKAHP NMEAGPPESG ESTDALKLCP HEEFLRLCKE
RAEEIYPIKE RNNRTRLALI ICNTEFDHLP PRNGADFDIT GMKELLEGLD YSVDVEENLT
ARDMESALRA FATRPEHKSS DSTFLVLMSH GILEGICGTV HDEKKPDVLL YDTIFQIFNN
RNCLSLKDKP KVIIVQACRG ANRGELWVRD SPASLEVASS QSSENLEEDA VYKTHVEKDF
IAFCSSTPHN VSWRDSTMGS IFITQLITCF QKYSWCCHLE EVFRKVQQSF ETPRAKAQMP
TIERLSMTRY FYLFPGN
