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 27-MAR-2024, entry version 215. 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:37993712, ECO:0000269|PubMed:37993714, 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 FUNCTION, AND ACTIVITY REGULATION. RX PubMed=29520027; DOI=10.1038/s41467-018-03409-3; RA Chu L.H., Indramohan M., Ratsimandresy R.A., Gangopadhyay A., Morris E.P., RA Monack D.M., Dorfleutner A., Stehlik C.; RT "The oxidized phospholipid oxPAPC protects from septic shock by targeting RT the non-canonical inflammasome in macrophages."; RL Nat. Commun. 9:996-996(2018). RN [34] RP FUNCTION. RX PubMed=31268602; DOI=10.15252/embj.2018100926; RA Fisch D., Bando H., Clough B., Hornung V., Yamamoto M., Shenoy A.R., RA Frickel E.M.; RT "Human GBP1 is a microbe-specific gatekeeper of macrophage apoptosis and RT pyroptosis."; RL EMBO J. 38:e100926-e100926(2019). RN [35] 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 [36] RP FUNCTION. RX PubMed=32510692; DOI=10.15252/embj.2020104926; RA Kutsch M., Sistemich L., Lesser C.F., Goldberg M.B., Herrmann C., Coers J.; RT "Direct binding of polymeric GBP1 to LPS disrupts bacterial cell envelope RT functions."; RL EMBO J. 39:e104926-e104926(2020). RN [37] RP FUNCTION. RX PubMed=32581219; DOI=10.1038/s41467-020-16889-z; RA Santos J.C., Boucher D., Schneider L.K., Demarco B., Dilucca M., RA Shkarina K., Heilig R., Chen K.W., Lim R.Y.H., Broz P.; RT "Human GBP1 binds LPS to initiate assembly of a caspase-4 activating RT platform on cytosolic bacteria."; RL Nat. Commun. 11:3276-3276(2020). RN [38] 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 [39] 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 [40] RP ADP-RIBOXANATION AT ARG-314 (MICROBIAL INFECTION). RX PubMed=35338844; DOI=10.1016/j.molcel.2022.03.010; RA Peng T., Tao X., Xia Z., Hu S., Xue J., Zhu Q., Pan X., Zhang Q., Li S.; RT "Pathogen hijacks programmed cell death signaling by arginine ADPR- RT deacylization of caspases."; RL Mol. Cell 82:1806-1820(2022). RN [41] RP FUNCTION, AND IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=37001519; DOI=10.1016/j.immuni.2023.03.003; RA Zhu F., Ma J., Li W., Liu Q., Qin X., Qian Y., Wang C., Zhang Y., Li Y., RA Jiang D., Wang S., Xia P.; RT "The orphan receptor Nur77 binds cytoplasmic LPS to activate the non- RT canonical NLRP3 inflammasome."; RL Immunity 56:753-767(2023). RN [42] RP ADP-RIBOXANATION (MICROBIAL INFECTION). RX PubMed=37014865; DOI=10.1073/pnas.2218469120; RA Goers L., Kim K., Stedman T.C., Canning P.J., Mou X., Ernst N.H., Coers J., RA Lesser C.F.; RT "Shigella IpaH9.8 limits GBP1-dependent LPS release from intracytosolic RT bacteria to suppress caspase-4 activation."; RL Proc. Natl. Acad. Sci. U.S.A. 120:e2218469120-e2218469120(2023). RN [43] {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). RN [44] {ECO:0007744|PDB:7WR0, ECO:0007744|PDB:7WR1, ECO:0007744|PDB:7WR4, ECO:0007744|PDB:7WR5, ECO:0007744|PDB:7WR6} RP X-RAY CRYSTALLOGRAPHY (1.96 ANGSTROMS) OF 102-377 IN COMPLEX WITH RP CALMODULIN AND S.FLEXNERI OSPC3, AND ADP-RIBOXANATION AT ARG-314 (MICROBIAL RP INFECTION). RX PubMed=36624349; DOI=10.1038/s41594-022-00888-3; RA Hou Y., Zeng H., Li Z., Feng N., Meng F., Xu Y., Li L., Shao F., Ding J.; RT "Structural mechanisms of calmodulin activation of Shigella effector OspC3 RT to ADP-riboxanate caspase-4/11 and block pyroptosis."; RL Nat. Struct. Mol. Biol. 30:261-272(2023). RN [45] {ECO:0007744|PDB:8SPB} RP STRUCTURE BY ELECTRON MICROSCOPY (3.2 ANGSTROMS) OF 94-270 AND 290-377 IN RP COMPLEX WITH IL18, FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND RP MUTAGENESIS OF CYS-258; TRP-267; ARG-269 AND LYS-356. RX PubMed=37993712; DOI=10.1038/s41586-023-06751-9; RA Devant P., Dong Y., Mintseris J., Ma W., Gygi S.P., Wu H., Kagan J.C.; RT "Structural insights into cytokine cleavage by inflammatory caspase-4."; RL Nature 0:0-0(2023). RN [46] {ECO:0007744|PDB:8J6K} RP X-RAY CRYSTALLOGRAPHY (3.12 ANGSTROMS) OF 102-270 AND 290-377 IN COMPLEX RP WITH IL18 AND S.FLEXNERI OSPC3, FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, RP PROTEOLYTIC CLEAVAGE, ACTIVE SITE, AND MUTAGENESIS OF ARG-152; ILE-212; RP CYS-258; ALA-261; TRP-267; ASP-289; VAL-291; LYS-293; ARG-314 AND ILE-321. RX PubMed=37993714; DOI=10.1038/s41586-023-06742-w; RA Shi X., Sun Q., Hou Y., Zeng H., Cao Y., Dong M., Ding J., Shao F.; RT "Recognition and maturation of IL-18 by caspase-4 noncanonical RT inflammasome."; RL Nature 0:0-0(2023). CC -!- FUNCTION: Inflammatory caspase that acts as the effector of the non- CC canonical inflammasome by mediating lipopolysaccharide (LPS)-induced CC pyroptosis (PubMed:25119034, PubMed:26375003, PubMed:34671164, CC PubMed:32109412, PubMed:37001519, PubMed:37993712, PubMed:37993714). CC Also indirectly activates the NLRP3 and NLRP6 inflammasomes CC (PubMed:7797510, PubMed:23516580, PubMed:26375003, PubMed:32109412). CC Acts as a thiol protease that cleaves a tetrapeptide after an Asp CC residue at position P1: catalyzes cleavage of CGAS, GSDMD and IL18 CC (PubMed:7797510, PubMed:15326478, PubMed:23516580, PubMed:26375003, CC PubMed:28314590, PubMed:32109412, PubMed:37993712, PubMed:37993714). CC Effector of the non-canonical inflammasome independently of NLRP3 CC inflammasome and CASP1: the non-canonical inflammasome promotes CC pyroptosis through GSDMD cleavage without involving secretion of CC cytokine IL1B (PubMed:25121752, PubMed:25119034, PubMed:26375003, CC PubMed:31268602, PubMed:32109412, PubMed:37993712, PubMed:37993714). In CC the non-canonical inflammasome, CASP4 is activated by direct binding to CC the lipid A moiety of LPS without the need of an upstream sensor CC (PubMed:25121752, PubMed:25119034, PubMed:29520027, PubMed:32510692, CC PubMed:32581219, PubMed:37993712). LPS-binding promotes CASP4 CC activation and CASP4-mediated cleavage of GSDMD and IL18, followed by CC IL18 secretion through the GSDMD pore, pyroptosis of infected cells and CC their extrusion into the gut lumen (PubMed:25121752, PubMed:25119034, CC PubMed:37993712, PubMed:37993714). Also indirectly promotes secretion CC of mature cytokines (IL1A and HMGB1) downstream of GSDMD-mediated CC pyroptosis via activation of the NLRP3 and NLRP6 inflammasomes CC (PubMed:26375003, PubMed:32109412). Involved in NLRP3-dependent CASP1 CC activation and IL1B secretion in response to non-canonical activators, CC such as UVB radiation or cholera enterotoxin (PubMed:22246630, CC PubMed:23516580, PubMed:24879791, PubMed:25964352, PubMed:26173988, CC PubMed:26174085, PubMed:26508369). Involved in NLRP6 inflammasome- CC dependent activation in response to lipoteichoic acid (LTA), a cell- CC wall component of Gram-positive bacteria, which leads to CASP1 CC activation and IL1B secretion (PubMed:33377178). Involved in LPS- CC induced IL6 secretion; this activity may not require caspase enzymatic CC activity (PubMed:26508369). The non-canonical inflammasome is required CC for innate immunity to cytosolic, but not vacuolar, bacteria (By CC similarity). Plays a crucial role in the restriction of S.typhimurium CC replication in colonic epithelial cells during infection CC (PubMed:25121752, PubMed:25964352). Pyroptosis limits bacterial CC replication, while cytokine secretion promotes the recruitment and CC activation of immune cells and triggers mucosal inflammation CC (PubMed:25121752, PubMed:26375003, PubMed:25964352). May also act as an CC activator of adaptive immunity in dendritic cells, following activation CC by oxidized phospholipid 1-palmitoyl-2-arachidonoyl- sn-glycero-3- CC phosphorylcholine, an oxidized phospholipid (oxPAPC) (By similarity). CC Involved in cell death induced by endoplasmic reticulum stress and by CC treatment with cytotoxic APP peptides found in Alzheimer's patient CC brains (PubMed:15123740, PubMed:22246630, PubMed:23661706). Cleavage of CC GSDMD is not strictly dependent on the consensus cleavage site but CC depends on an exosite interface on CASP4 that recognizes and binds the CC Gasdermin-D, C-terminal (GSDMD-CT) part (PubMed:32109412). Catalyzes CC cleavage and maturation of IL18; IL18 processing also depends of the CC exosite interface on CASP4 (PubMed:15326478, PubMed:37993712, CC PubMed:37993714). 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:29520027, CC ECO:0000269|PubMed:31268602, ECO:0000269|PubMed:32109412, CC ECO:0000269|PubMed:32510692, ECO:0000269|PubMed:32581219, CC ECO:0000269|PubMed:33377178, ECO:0000269|PubMed:34671164, CC ECO:0000269|PubMed:37001519, ECO:0000269|PubMed:37993714, 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:37993712, CC ECO:0000269|PubMed:37993714, 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, PubMed:29520027). In addition to LPS, CASP4/CASP11 CC may also be activated by oxidized phospholipid 1-palmitoyl-2- CC arachidonoyl- sn-glycero-3-phosphorylcholine, an oxidized phospholipid CC (oxPAPC), in dendritic cells, promoting adaptive immunity (By CC similarity). The role of oxPAPC is however unclear and another report CC suggests that oxPAPC competes with LPS-binding and inhibits the non- CC canonical inflammasome in macrophages (PubMed:29520027). CC {ECO:0000250|UniProtKB:P70343, ECO:0000269|PubMed:25119034, CC ECO:0000269|PubMed:29520027}. 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, ECO:0000269|PubMed:37993714}. 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, ECO:0000269|PubMed:37993714}. 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, undergoes autoproteolytic CC cleavage and activation. {ECO:0000269|PubMed:15123740, CC ECO:0000269|PubMed:32109412, ECO:0000269|PubMed:34671164, CC ECO:0000269|PubMed:37993714, 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. {ECO:0000269|PubMed:34671164, CC ECO:0000269|PubMed:35338844, ECO:0000269|PubMed:36624349, CC ECO:0000269|PubMed:37014865}. 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=AAC99851.1; Type=Frameshift; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/casp4/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 PDB; 7WR0; X-ray; 2.80 A; A=102-377. DR PDB; 7WR1; X-ray; 2.13 A; A/B=102-377. DR PDB; 7WR4; X-ray; 2.75 A; C=102-377. DR PDB; 7WR5; X-ray; 3.10 A; C=102-377. DR PDB; 7WR6; X-ray; 1.96 A; A=102-377. DR PDB; 8J6K; X-ray; 3.12 A; A=102-270, a=290-377. DR PDB; 8SPB; EM; 3.20 A; A/a=94-270, B/b=290-377. DR PDBsum; 6KMZ; -. DR PDBsum; 6NRY; -. DR PDBsum; 7WR0; -. DR PDBsum; 7WR1; -. DR PDBsum; 7WR4; -. DR PDBsum; 7WR5; -. DR PDBsum; 7WR6; -. DR PDBsum; 8J6K; -. DR PDBsum; 8SPB; -. DR AlphaFoldDB; P49662; -. DR EMDB; EMD-40678; -. DR SMR; P49662; -. DR BioGRID; 107287; 47. 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; 9606-ENSP00000388566; -. DR PeptideAtlas; P49662; -. DR ProteomicsDB; 56043; -. [P49662-1] DR ProteomicsDB; 56044; -. [P49662-2] DR Pumba; P49662; -. DR Antibodypedia; 18094; 834 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 AGR; HGNC:1505; -. 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; ACRGANH; -. DR OrthoDB; 2873736at2759; -. DR PhylomeDB; P49662; -. DR TreeFam; TF102023; -. DR BioCyc; MetaCyc:HS06388-MONOMER; -. 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; 15 hits in 1158 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 178 other cell types or tissues. DR ExpressionAtlas; P49662; baseline and differential. DR GO; GO:0061702; C:canonical inflammasome complex; IEA:UniProtKB-SubCell. 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:0005739; C:mitochondrion; IDA:ParkinsonsUK-UCL. DR GO; GO:0160074; C:non-canonical inflammasome complex; IDA:UniProtKB. 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:0097200; F:cysteine-type endopeptidase activity involved in execution phase of apoptosis; IBA:GO_Central. DR GO; GO:0008289; F:lipid binding; IDA:UniProtKB. DR GO; GO:0001530; F:lipopolysaccharide binding; IDA:UniProtKB. 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:0042742; P:defense response to bacterium; IDA:UniProtKB. 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:0160075; P:non-canonical 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: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:0051604; P:protein maturation; IDA:UniProt. 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; cd08325; CARD_CASP1-like; 1. DR CDD; cd00032; CASc; 1. DR Gene3D; 3.40.50.1460; -; 1. DR Gene3D; 1.10.533.10; Death Domain, Fas; 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; IPR011600; Pept_C14_caspase. DR InterPro; IPR002138; Pept_C14_p10. DR InterPro; IPR001309; Pept_C14_p20. DR InterPro; IPR015917; Pept_C14A. DR PANTHER; PTHR47901; CASPASE RECRUITMENT DOMAIN-CONTAINING PROTEIN 18; 1. DR PANTHER; PTHR47901:SF3; CASPASE-1; 1. DR Pfam; PF00619; CARD; 1. DR Pfam; PF00656; Peptidase_C14; 1. DR PIRSF; PIRSF038001; Caspase_ICE; 1. DR PRINTS; PR00376; IL1BCENZYME. DR SMART; SM00114; CARD; 1. DR SMART; SM00115; CASc; 1. DR SUPFAM; SSF52129; Caspase-like; 1. DR SUPFAM; SSF47986; DEATH domain; 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. DR Genevisible; P49662; HS. 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 ECO:0000305|PubMed:37993714" 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 ECO:0000305|PubMed:37993714" 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:37993712, ECO:0000269|PubMed:37993714, FT ECO:0000269|PubMed:7743998" FT SITE 289..290 FT /note="Cleavage; by autolysis" FT /evidence="ECO:0000269|PubMed:37993714, FT 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 ECO:0000269|PubMed:35338844, ECO:0000269|PubMed:36624349" 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 152 FT /note="R->A: Abolished ability to cleave IL18." FT /evidence="ECO:0000269|PubMed:37993714" FT MUTAGEN 212 FT /note="I->D: Abolished ability to cleave IL18; when FT associated with D-261." FT /evidence="ECO:0000269|PubMed:37993714" FT MUTAGEN 258 FT /note="C->A: Loss of enzymatic activity. Loss of FT LPS-induced pyroptosis. No effect on the interaction with FT LPS. Decrease in cell death induced by TMEM214 FT overexpression. Does not support IL1B and IL18 secretion FT following UVB irradiation." FT /evidence="ECO:0000269|PubMed:22246630, FT ECO:0000269|PubMed:23661706, ECO:0000269|PubMed:25119034, FT ECO:0000269|PubMed:28314590, ECO:0000269|PubMed:37993712, FT ECO:0000269|PubMed:37993714" FT MUTAGEN 258 FT /note="C->S: Loss of autocatalysis." FT /evidence="ECO:0000269|PubMed:7743998" FT MUTAGEN 261 FT /note="A->D: Abolished ability to cleave IL18; when FT associated with D-212." FT /evidence="ECO:0000269|PubMed:37993714" FT MUTAGEN 267 FT /note="W->L,N: Abolished interaction with Gasdermin-D FT (GSDMD) and ability to mediate its cleavage. Abolished FT binding to IL18 and ability to mediate its cleavage." FT /evidence="ECO:0000269|PubMed:32109412, FT ECO:0000269|PubMed:37993712, ECO:0000269|PubMed:37993714" FT MUTAGEN 269 FT /note="R->D: Abolished binding to IL18 and ability to FT mediate its cleavage." FT /evidence="ECO:0000269|PubMed:37993712" 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 289 FT /note="D->A: Abolished autoprocessing." FT /evidence="ECO:0000269|PubMed:37993714" FT MUTAGEN 291 FT /note="V->N: Abolished interaction with Gasdermin-D (GSDMD) FT and ability to mediate its cleavage. Strongly decreased FT ability to cleave IL18." FT /evidence="ECO:0000269|PubMed:32109412, FT ECO:0000269|PubMed:37993714" FT MUTAGEN 293 FT /note="K->A: Strongly decreased ability to cleave IL18." FT /evidence="ECO:0000269|PubMed:37993714" FT MUTAGEN 314 FT /note="R->A: Abolished ability to cleave Gasdermin-D FT (GSDMD). Abolished ability to cleave IL18." FT /evidence="ECO:0000269|PubMed:34671164, FT ECO:0000269|PubMed:37993714" FT MUTAGEN 321 FT /note="I->D: Abolished ability to cleave IL18." FT /evidence="ECO:0000269|PubMed:37993714" FT MUTAGEN 356 FT /note="K->D: Abolished binding to IL18 and ability to FT mediate its cleavage." FT /evidence="ECO:0000269|PubMed:37993712" FT HELIX 111..120 FT /evidence="ECO:0007829|PDB:7WR6" FT HELIX 122..124 FT /evidence="ECO:0007829|PDB:7WR6" FT HELIX 131..133 FT /evidence="ECO:0007829|PDB:7WR6" FT STRAND 136..142 FT /evidence="ECO:0007829|PDB:7WR6" FT STRAND 147..149 FT /evidence="ECO:0007829|PDB:7WR6" FT HELIX 155..168 FT /evidence="ECO:0007829|PDB:7WR6" FT STRAND 171..178 FT /evidence="ECO:0007829|PDB:7WR6" FT HELIX 181..192 FT /evidence="ECO:0007829|PDB:7WR6" FT HELIX 195..197 FT /evidence="ECO:0007829|PDB:7WR6" FT STRAND 203..211 FT /evidence="ECO:0007829|PDB:7WR6" FT STRAND 213..217 FT /evidence="ECO:0007829|PDB:7WR6" FT STRAND 223..225 FT /evidence="ECO:0007829|PDB:7WR6" FT STRAND 228..230 FT /evidence="ECO:0007829|PDB:7WR6" FT HELIX 231..237 FT /evidence="ECO:0007829|PDB:7WR6" FT TURN 240..242 FT /evidence="ECO:0007829|PDB:7WR6" FT HELIX 244..246 FT /evidence="ECO:0007829|PDB:7WR6" FT STRAND 251..259 FT /evidence="ECO:0007829|PDB:7WR6" FT HELIX 293..296 FT /evidence="ECO:0007829|PDB:7WR6" FT STRAND 299..305 FT /evidence="ECO:0007829|PDB:7WR6" FT HELIX 309..311 FT /evidence="ECO:0007829|PDB:7WR0" FT HELIX 313..316 FT /evidence="ECO:0007829|PDB:6NRY" FT STRAND 317..320 FT /evidence="ECO:0007829|PDB:7WR0" FT HELIX 321..333 FT /evidence="ECO:0007829|PDB:7WR6" FT TURN 334..336 FT /evidence="ECO:0007829|PDB:7WR6" FT HELIX 339..349 FT /evidence="ECO:0007829|PDB:7WR6" FT TURN 353..355 FT /evidence="ECO:0007829|PDB:7WR6" FT HELIX 356..358 FT /evidence="ECO:0007829|PDB:7WR6" FT STRAND 361..364 FT /evidence="ECO:0007829|PDB:7WR6" FT STRAND 368..370 FT /evidence="ECO:0007829|PDB:7WR6" 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 //