CASP4_MOUSE
ID CASP4_MOUSE Reviewed; 373 AA.
AC P70343; C6L648; O08735; Q3TAF3; Q6P8H1;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 2.
DT 03-AUG-2022, entry version 184.
DE RecName: Full=Caspase-4;
DE Short=CASP-4;
DE EC=3.4.22.64 {ECO:0000250|UniProtKB:P49662};
DE AltName: Full=Caspase-11 {ECO:0000303|Ref.3};
DE Short=CASP-11 {ECO:0000303|Ref.3};
DE AltName: Full=Protease ICH-3 {ECO:0000303|PubMed:8702803};
DE Contains:
DE RecName: Full=Caspase-4 subunit p10 {ECO:0000305|PubMed:32109412};
DE Contains:
DE RecName: Full=Caspase-4 subunit p20 {ECO:0000305|PubMed:32109412};
DE Flags: Precursor;
GN Name=Casp4 {ECO:0000312|MGI:MGI:107700};
GN Synonyms=Casp11 {ECO:0000303|PubMed:30392956, ECO:0000303|Ref.3}, Caspl,
GN Ich3 {ECO:0000303|PubMed:8702803};
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), FUNCTION, INDUCTION BY LPS, AND
RP TISSUE SPECIFICITY.
RC STRAIN=C57BL/6 X CBA; TISSUE=Thymus;
RX PubMed=8702803; DOI=10.1074/jbc.271.34.20580;
RA Wang S., Miura M., Jung Y.-K., Zhu H., Gagliardini V., Shi L.,
RA Greenberg A.H., Yuan J.;
RT "Identification and characterization of Ich-3, a member of the interleukin-
RT 1beta converting enzyme (ICE)/Ced-3 family and an upstream regulator of
RT ICE.";
RL J. Biol. Chem. 271:20580-20587(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND TISSUE SPECIFICITY.
RC STRAIN=C3H/An; TISSUE=Fibrosarcoma;
RX PubMed=9038361; DOI=10.1016/s0014-5793(97)00026-4;
RA van de Craen M., Vandenabeele P., Declercq W., van den Brande I.,
RA van Loo G., Molemans F., Schotte P., van Criekinge W., Beyaert R.,
RA Fiers W.;
RT "Characterization of seven murine caspase family members.";
RL FEBS Lett. 403:61-69(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC STRAIN=C57BL/6J;
RA Endo M., Nakayama Y., Mori M., Oike Y., Gotoh T.;
RT "ER stress-mediated caspase-11 induction is regulated with alternative
RT splicing.";
RL Submitted (FEB-2009) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=C57BL/6J, and NOD; TISSUE=Bone marrow, and Spleen;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Pituitary;
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 [8]
RP INDUCTION BY LPS.
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 [9]
RP INDUCTION BY LPS AND ER STRESS, AND SUBCELLULAR LOCATION.
RX PubMed=16670335; DOI=10.4049/jimmunol.176.10.6245;
RA Endo M., Mori M., Akira S., Gotoh T.;
RT "C/EBP homologous protein (CHOP) is crucial for the induction of caspase-11
RT and the pathogenesis of lipopolysaccharide-induced inflammation.";
RL J. Immunol. 176:6245-6253(2006).
RN [10]
RP FUNCTION, DISRUPTION PHENOTYPE, INDUCTION BY LPS AND LIVE E.COLI,
RP STRAIN-SPECIFIC VARIANT, PROTEOLYTIC CLEAVAGE, AND MUTAGENESIS OF CYS-254.
RX PubMed=22002608; DOI=10.1038/nature10558;
RA Kayagaki N., Warming S., Lamkanfi M., Vande Walle L., Louie S., Dong J.,
RA Newton K., Qu Y., Liu J., Heldens S., Zhang J., Lee W.P., Roose-Girma M.,
RA Dixit V.M.;
RT "Non-canonical inflammasome activation targets caspase-11.";
RL Nature 479:117-121(2011).
RN [11]
RP FUNCTION.
RX PubMed=23348507; DOI=10.1126/science.1230751;
RA Aachoui Y., Leaf I.A., Hagar J.A., Fontana M.F., Campos C.G., Zak D.E.,
RA Tan M.H., Cotter P.A., Vance R.E., Aderem A., Miao E.A.;
RT "Caspase-11 protects against bacteria that escape the vacuole.";
RL Science 339:975-978(2013).
RN [12]
RP FUNCTION, DISRUPTION PHENOTYPE, AND PROTEOLYTIC CLEAVAGE.
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 [13]
RP FUNCTION, ACTIVITY REGULATION, OLIGOMERIZATION, INTERACTION WITH LPS,
RP DOMAIN, AND MUTAGENESIS OF LYS-19; LYS-38; GLU-40; LYS-53; ARG-54; TRP-55;
RP LYS-62; LYS-63; LYS-64 AND CYS-254.
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 [14]
RP DISRUPTION PHENOTYPE, AND INDUCTION BY POLY(I:C).
RX PubMed=26320999; DOI=10.1016/j.chom.2015.07.016;
RA Aachoui Y., Kajiwara Y., Leaf I.A., Mao D., Ting J.P., Coers J., Aderem A.,
RA Buxbaum J.D., Miao E.A.;
RT "Canonical inflammasomes drive IFN-gamma to prime caspase-11 in defense
RT against a cytosol-invasive bacterium.";
RL Cell Host Microbe 18:320-332(2015).
RN [15]
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 [16]
RP INDUCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=26375259; DOI=10.1038/nature15541;
RA Kayagaki N., Stowe I.B., Lee B.L., O'Rourke K., Anderson K., Warming S.,
RA Cuellar T., Haley B., Roose-Girma M., Phung Q.T., Liu P.S., Lill J.R.,
RA Li H., Wu J., Kummerfeld S., Zhang J., Lee W.P., Snipas S.J.,
RA Salvesen G.S., Morris L.X., Fitzgerald L., Zhang Y., Bertram E.M.,
RA Goodnow C.C., Dixit V.M.;
RT "Caspase-11 cleaves gasdermin D for non-canonical inflammasome
RT signalling.";
RL Nature 526:666-671(2015).
RN [17]
RP FUNCTION, AND MUTAGENESIS OF CYS-254.
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 [18]
RP FUNCTION, PROTEOLYTIC CLEAVAGE, AND MUTAGENESIS OF ASP-80; CYS-254; ASP-277
RP AND ASP-285.
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 [19]
RP FUNCTION, AND INTERACTION WITH SERPINB1A; SERPINB1B AND SERPINB1C.
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 [20]
RP FUNCTION.
RX PubMed=32554464; DOI=10.1074/jbc.ra120.014259;
RA Bibo-Verdugo B., Snipas S.J., Kolt S., Poreba M., Salvesen G.S.;
RT "Extended subsite profiling of the pyroptosis effector protein gasdermin D
RT reveals a region recognized by inflammatory caspase-11.";
RL J. Biol. Chem. 295:11292-11302(2020).
RN [21]
RP FUNCTION, ADP-RIBOXANATION AT ARG-310 (MICROBIAL INFECTION), AND
RP MUTAGENESIS OF ARG-310.
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 [22] {ECO:0007744|PDB:6KMT, ECO:0007744|PDB:6KMU, ECO:0007744|PDB:6KMV, ECO:0007744|PDB:6KN1}
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) OF 102-265; 287-373; 110-264 AND
RP 286-373 IN COMPLEX WITH GSDMD, FUNCTION, SUBUNIT, AND PROTEOLYTIC CLEAVAGE.
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:23348507, PubMed:30392956). Thiol
CC protease that cleaves a tetrapeptide after an Asp residue at position
CC P1: catalyzes cleavage of CGAS, GSDMD and IL18 (PubMed:26375003,
CC PubMed:30392956). Required for innate immunity to cytosolic, but not
CC vacuolar, bacteria (PubMed:23348507). Plays a key role in NLRP3-
CC dependent CASP1 activation and IL1B and IL18 secretion in response to
CC non-canonical activators, such as UVB radiation, cholera enterotoxin
CC subunit B and cytosolic LPS (PubMed:8702803, PubMed:9038361,
CC PubMed:22002608, PubMed:25119034). Activated by direct binding to LPS
CC without the need of an upstream sensor (PubMed:25119034). Involved in
CC NLRP6 inflammasome-dependent activation in response to lipoteichoic
CC acid (LTA), a cell-wall component of Gram-positive bacteria, which
CC leads to CASP1 activation and IL1B and IL18 secretion
CC (PubMed:30392956). Independently of NLRP3 inflammasome and CASP1,
CC promotes pyroptosis, through GSDMD cleavage and activation, followed by
CC IL1A, IL18 and HMGB1 release in response to non-canonical inflammasome
CC activators (PubMed:22002608, PubMed:23348507, PubMed:26320999,
CC PubMed:26375003). 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:34671164). Cleavage of GSDMD is not strictly dependent on the
CC consensus cleavage site but depends on an exosite interface on CASP4
CC that recognizes and binds the Gasdermin-D, C-terminal (GSDMD-CT) part
CC (PubMed:32109412, PubMed:32554464). Pyroptosis limits bacterial
CC replication, while cytokine secretion promotes the recruitment and
CC activation of immune cells and triggers mucosal inflammation
CC (PubMed:25121752). Involved in LPS-induced IL6 secretion; this activity
CC may not require caspase enzymatic activity (By similarity). Catalyzes
CC cleavage and maturation of IL18 (By similarity). In contrast, it does
CC not directly process IL1B (PubMed:8702803, PubMed:9038361). During non-
CC canonical inflammasome activation, cuts CGAS and may play a role in the
CC regulation of antiviral innate immune activation (PubMed:28314590).
CC {ECO:0000250|UniProtKB:P49662, ECO:0000269|PubMed:22002608,
CC ECO:0000269|PubMed:23348507, ECO:0000269|PubMed:25119034,
CC ECO:0000269|PubMed:25121752, ECO:0000269|PubMed:26320999,
CC ECO:0000269|PubMed:26375003, ECO:0000269|PubMed:28314590,
CC ECO:0000269|PubMed:30392956, ECO:0000269|PubMed:32109412,
CC ECO:0000269|PubMed:32554464, ECO:0000269|PubMed:34671164,
CC ECO:0000269|PubMed:8702803, ECO:0000269|PubMed:9038361}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Strict requirement for Asp at the P1 position and has a
CC preferred cleavage sequence of (Ile/Leu/Val/Phe)-Gly-His-Asp-|-.;
CC EC=3.4.22.64; Evidence={ECO:0000250|UniProtKB:P49662};
CC -!- ACTIVITY REGULATION: Activated by homooligomerization induced by direct
CC binding to cytosolic LPS, in a TLR4-independent manner.
CC {ECO:0000269|PubMed:25119034}.
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.
CC These oligomers are often referred to as 'non-canonical inflammasomes'
CC (PubMed:25119034). In its precursor form, interacts with TMEM214; this
CC interaction is required for association with the endoplasmic reticulum
CC membrane (By similarity). Interacts with CASP1 (By similarity).
CC Interacts with NOD2 (By similarity). Interacts with Serpinb1a,
CC Serpinb1b and Serpinb1c; these interactions regulate CASP4 activity (By
CC similarity). {ECO:0000250|UniProtKB:P49662,
CC ECO:0000269|PubMed:25119034, 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 -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:P49662}. Cytoplasm
CC {ECO:0000269|PubMed:16670335}. Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:P49662}; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:P49662}; Cytoplasmic side
CC {ECO:0000250|UniProtKB:P49662}. Mitochondrion
CC {ECO:0000250|UniProtKB:P49662}. Inflammasome
CC {ECO:0000269|PubMed:25119034}. Secreted {ECO:0000250|UniProtKB:P49662}.
CC Note=Predominantly localizes to the endoplasmic reticulum (ER).
CC Association with the ER membrane requires TMEM214. Released in the
CC extracellular milieu by keratinocytes following UVB irradiation.
CC {ECO:0000250|UniProtKB:P49662}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P70343-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P70343-2; Sequence=VSP_058183, VSP_058184;
CC -!- TISSUE SPECIFICITY: Widely expressed, including in thymus, lung and
CC spleen (at protein level). Very low levels, if any, in the brain.
CC {ECO:0000269|PubMed:8702803, ECO:0000269|PubMed:9038361}.
CC -!- INDUCTION: Up-regulated by LPS and E.coli (PubMed:8702803,
CC PubMed:10986288, PubMed:22002608, PubMed:26375259). In LPS-induced lung
CC inflammation, markedly up-regulated after 6 hours of treatment and
CC decreases at 24 hours. The induction is dependent upon DDIT3/CHOP-
CC mediated ER stress (at protein level) (PubMed:16670335). In the spleen
CC and in bone marrow-derived macrophages, up-regulated by poly(I:C), a
CC synthetic analog of double-stranded RNA (at protein level)
CC (PubMed:26320999, PubMed:26375259). Also induced by IFNG and
CC interferon-alpha. Up-regulated by R848, a TLR7 synthetic activator, and
CC Pam3CysK4, a synthetic activator of TLR1/TLR2 (PubMed:26375259).
CC {ECO:0000269|PubMed:10986288, ECO:0000269|PubMed:16670335,
CC ECO:0000269|PubMed:22002608, ECO:0000269|PubMed:26320999,
CC ECO:0000269|PubMed:26375259, ECO:0000269|PubMed:8702803}.
CC -!- DOMAIN: The CARD domain mediates LPS recognition and
CC homooligomerization. {ECO:0000269|PubMed:25119034}.
CC -!- PTM: In response to activation signals, including cholera enterotoxin
CC subunit B, infection by E. coli or S. typhimurium or endoplasmic
CC reticulum stress, undergoes autoproteolytic cleavage.
CC {ECO:0000269|PubMed:22002608, ECO:0000269|PubMed:25121752,
CC ECO:0000269|PubMed:30392956, ECO:0000269|PubMed:32109412}.
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 -!- POLYMORPHISM: A variant of this gene has been observed in several 129
CC substrains, including 129/SvJ, 129S1/Sv, 129P3/J and 129S6/SvEvTac.
CC This variant displays a 5-bp deletion encompassing the exon 7 splice
CC acceptor junction. As a result, exon 7 is spliced out. Joining of exon
CC 6 to exon 8 creates a frameshift after Pro-304 and a stop codon occurs
CC after 5 aberrant amino acids. The mRNA may be the target of nonsense-
CC mediated mRNA decay. It is detected only at low levels, while the
CC corresponding protein is not detected at all in any of the 129
CC substrains tested. {ECO:0000269|PubMed:22002608}.
CC -!- DISRUPTION PHENOTYPE: Mutant animals are largely resistant to LPS-
CC induced lethal septic shock (PubMed:22002608, PubMed:26375259).
CC However, they are susceptible to Burkholderia thailandensis infection,
CC even at low bacterial doses (PubMed:26320999). During intestinal
CC Salmonella Typhimurium infection, mutant animals display higher
CC pathogen loads in their cecal tissues and lumen and lower levels of
CC IL18 in cecal explants, associated with a significant reduction in
CC cecal inflammation (PubMed:25121752). Bone-marrow-derived macrophages
CC from knockout mice respond normally, in terms of IL1B secretion, to
CC canonical inflammasome activators, such as ATP, monosodium urate,
CC poly(dA:dT) double-stranded DNA, Francisella tularensis, flagellin or
CC Pseudomonas aeruginosa, but fail to secrete IL1B in response to cholera
CC enterotoxin subunit B. They also do not respond to live E. coli, C.
CC rodentium and V. cholerae, with or without LPS priming
CC (PubMed:22002608). {ECO:0000269|PubMed:22002608,
CC ECO:0000269|PubMed:25121752, ECO:0000269|PubMed:26320999,
CC ECO:0000269|PubMed:26375259}.
CC -!- MISCELLANEOUS: [Isoform 2]: May be produced at very low levels due to a
CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA
CC decay. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the peptidase C14A family. {ECO:0000305}.
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DR EMBL; U59463; AAB09469.1; -; mRNA.
DR EMBL; Y13089; CAA73531.1; -; mRNA.
DR EMBL; AB480706; BAH96541.1; -; mRNA.
DR EMBL; AK151547; BAE30493.1; -; mRNA.
DR EMBL; AK171877; BAE42715.1; -; mRNA.
DR EMBL; AC141637; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH466636; EDL09318.1; -; Genomic_DNA.
DR EMBL; BC061255; AAH61255.1; -; mRNA.
DR CCDS; CCDS22799.1; -. [P70343-1]
DR RefSeq; NP_031635.2; NM_007609.3. [P70343-1]
DR PDB; 6KMT; X-ray; 2.60 A; A/B/C/D=101-373.
DR PDB; 6KMU; X-ray; 2.10 A; A/E=102-285, B/F/H=288-373, C=101-285, D=287-373, G=101-254.
DR PDB; 6KMV; X-ray; 3.35 A; A=118-278, B/V=101-267, E/F/Z/d=101-266, I/M/N/Q/Y=102-266, J=118-266, R/c=118-267, U=101-265, g/h/i/j/k/l/m/n/o/p/q/r/t/u/v=286-373, s=287-373.
DR PDB; 6KN1; X-ray; 1.90 A; A=102-265, B=287-373, C=110-264, D=286-373.
DR PDB; 6NS7; X-ray; 2.40 A; A/B/C/D=92-373.
DR PDBsum; 6KMT; -.
DR PDBsum; 6KMU; -.
DR PDBsum; 6KMV; -.
DR PDBsum; 6KN1; -.
DR PDBsum; 6NS7; -.
DR AlphaFoldDB; P70343; -.
DR SMR; P70343; -.
DR DIP; DIP-61776N; -.
DR IntAct; P70343; 2.
DR STRING; 10090.ENSMUSP00000027012; -.
DR BindingDB; P70343; -.
DR ChEMBL; CHEMBL1075276; -.
DR MEROPS; C14.012; -.
DR PhosphoSitePlus; P70343; -.
DR EPD; P70343; -.
DR MaxQB; P70343; -.
DR PaxDb; P70343; -.
DR PRIDE; P70343; -.
DR ProteomicsDB; 265438; -. [P70343-1]
DR ProteomicsDB; 265439; -. [P70343-2]
DR DNASU; 12363; -.
DR Ensembl; ENSMUST00000027012; ENSMUSP00000027012; ENSMUSG00000033538. [P70343-1]
DR Ensembl; ENSMUST00000160064; ENSMUSP00000124249; ENSMUSG00000033538. [P70343-2]
DR GeneID; 12363; -.
DR KEGG; mmu:12363; -.
DR UCSC; uc009obt.3; mouse. [P70343-1]
DR CTD; 837; -.
DR MGI; MGI:107700; Casp4.
DR VEuPathDB; HostDB:ENSMUSG00000033538; -.
DR eggNOG; KOG3573; Eukaryota.
DR GeneTree; ENSGT00940000162428; -.
DR HOGENOM; CLU_036904_0_1_1; -.
DR InParanoid; P70343; -.
DR OMA; GEMWIRE; -.
DR OrthoDB; 1327703at2759; -.
DR PhylomeDB; P70343; -.
DR TreeFam; TF102023; -.
DR BRENDA; 3.4.22.57; 3474.
DR BRENDA; 3.4.22.64; 3474.
DR Reactome; R-MMU-168638; NOD1/2 Signaling Pathway.
DR Reactome; R-MMU-5620971; Pyroptosis.
DR BioGRID-ORCS; 12363; 3 hits in 60 CRISPR screens.
DR ChiTaRS; Casp4; mouse.
DR PRO; PR:P70343; -.
DR Proteomes; UP000000589; Chromosome 9.
DR RNAct; P70343; protein.
DR Bgee; ENSMUSG00000033538; Expressed in granulocyte and 105 other tissues.
DR ExpressionAtlas; P70343; baseline and differential.
DR Genevisible; P70343; MM.
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; ISO:MGI.
DR GO; GO:0005783; C:endoplasmic reticulum; ISO:MGI.
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; ISO:MGI.
DR GO; GO:0043005; C:neuron projection; IEA:Ensembl.
DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR GO; GO:0072558; C:NLRP1 inflammasome complex; ISO:MGI.
DR GO; GO:0072559; C:NLRP3 inflammasome complex; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0050700; F:CARD domain binding; ISO:MGI.
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:0097110; F:scaffold protein binding; IEA:Ensembl.
DR GO; GO:0007015; P:actin filament organization; TAS:UniProtKB.
DR GO; GO:0042742; P:defense response to bacterium; IMP:UniProtKB.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IDA:UniProtKB.
DR GO; GO:0035234; P:ectopic germ cell programmed cell death; IMP:MGI.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0050729; P:positive regulation of inflammatory response; IDA:UniProtKB.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IGI:MGI.
DR GO; GO:2000494; P:positive regulation of interleukin-18-mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:0060907; P:positive regulation of macrophage cytokine production; IGI:MGI.
DR GO; GO:0016540; P:protein autoprocessing; IDA:UniProtKB.
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; Alternative splicing; Cytoplasm; Endoplasmic reticulum;
KW Hydrolase; Immunity; Inflammasome; Inflammatory response; Innate immunity;
KW Membrane; Mitochondrion; Necrosis; Phosphoprotein; Protease;
KW Reference proteome; Secreted; Thiol protease; Zymogen.
FT PROPEP 1..80
FT /evidence="ECO:0000255"
FT /id="PRO_0000004600"
FT CHAIN 81..266
FT /note="Caspase-4 subunit p20"
FT /evidence="ECO:0000305|PubMed:32109412"
FT /id="PRO_0000004601"
FT PROPEP 267..285
FT /evidence="ECO:0000255"
FT /id="PRO_0000004602"
FT CHAIN 286..373
FT /note="Caspase-4 subunit p10"
FT /evidence="ECO:0000305|PubMed:32109412"
FT /id="PRO_0000004603"
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:0000269|PubMed:25119034"
FT ACT_SITE 206
FT /evidence="ECO:0000250|UniProtKB:P29466"
FT ACT_SITE 254
FT /evidence="ECO:0000250|UniProtKB:P49662"
FT MOD_RES 83
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P49662"
FT MOD_RES 310
FT /note="(Microbial infection) ADP-riboxanated arginine"
FT /evidence="ECO:0000269|PubMed:34671164"
FT VAR_SEQ 88..118
FT /note="ANLEMEEPEESLNTLKLCSPEEFTRLCREKT -> DLPNKGGQWPYTKGSYH
FT MQYRVQTSLTEVWG (in isoform 2)"
FT /evidence="ECO:0000303|Ref.3"
FT /id="VSP_058183"
FT VAR_SEQ 119..373
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.3"
FT /id="VSP_058184"
FT MUTAGEN 19
FT /note="K->E: Severely attenuated LPS-binding, LPS-induced
FT oligomerization and activation, and LPS-induced
FT pyroptosis."
FT /evidence="ECO:0000269|PubMed:25119034"
FT MUTAGEN 38
FT /note="K->E: No effect on LPS-binding, LPS-induced
FT oligomerization, and LPS-induced pyroptosis; when
FT associated with M-40."
FT /evidence="ECO:0000269|PubMed:25119034"
FT MUTAGEN 40
FT /note="E->M: No effect on LPS-binding, LPS-induced
FT oligomerization, and LPS-induced pyroptosis; when
FT associated with E-38."
FT /evidence="ECO:0000269|PubMed:25119034"
FT MUTAGEN 53
FT /note="K->E: Complete loss of LPS-binding, LPS-induced
FT oligomerization, and LPS-induced pyroptosis; when
FT associated with E-54 and A-55."
FT /evidence="ECO:0000269|PubMed:25119034"
FT MUTAGEN 54
FT /note="R->E: Complete loss of LPS-binding, LPS-induced
FT oligomerization, and LPS-induced pyroptosis; when
FT associated with E-53 and A-55."
FT /evidence="ECO:0000269|PubMed:25119034"
FT MUTAGEN 55
FT /note="W->A: Complete loss of LPS-binding, LPS-induced
FT oligomerization, and LPS-induced pyroptosis; when
FT associated with E-54 and A-55."
FT /evidence="ECO:0000269|PubMed:25119034"
FT MUTAGEN 62
FT /note="K->E: Severely attenuated LPS-binding, LPS-induced
FT oligomerization and activation, and LPS-induced pyroptosis;
FT when associated with E-63 and E-64."
FT /evidence="ECO:0000269|PubMed:25119034"
FT MUTAGEN 63
FT /note="K->E: Severely attenuated LPS-binding, LPS-induced
FT oligomerization and activation, and LPS-induced pyroptosis;
FT when associated with E-62 and E-64."
FT /evidence="ECO:0000269|PubMed:25119034"
FT MUTAGEN 64
FT /note="K->E: Severely attenuated LPS-binding, LPS-induced
FT oligomerization and activation, and LPS-induced pyroptosis;
FT when associated with E-62 and E-63."
FT /evidence="ECO:0000269|PubMed:25119034"
FT MUTAGEN 80
FT /note="D->N: Impaired NLRP6 inflammasome-dependent
FT activation and release of IL1B and IL18."
FT /evidence="ECO:0000269|PubMed:30392956"
FT MUTAGEN 254
FT /note="C->A: Loss of catalytic activity and of
FT autocatalytic processing. Loss of LPS-induced pyroptosis.
FT No effect on the interaction with LPS."
FT /evidence="ECO:0000269|PubMed:22002608,
FT ECO:0000269|PubMed:25119034, ECO:0000269|PubMed:28314590,
FT ECO:0000269|PubMed:30392956"
FT MUTAGEN 254
FT /note="C->G: No cell death."
FT MUTAGEN 277
FT /note="D->N: Impaired NLRP6 inflammasome-dependent
FT activation and release of IL1B and IL18."
FT /evidence="ECO:0000269|PubMed:30392956"
FT MUTAGEN 285
FT /note="D->N: Impaired NLRP6 inflammasome-dependent
FT activation and release of IL1B and IL18."
FT /evidence="ECO:0000269|PubMed:30392956"
FT MUTAGEN 310
FT /note="R->A: Abolished ability to cleave Gasdermin-D
FT (GSDMD)."
FT /evidence="ECO:0000269|PubMed:34671164"
FT CONFLICT 126
FT /note="E -> K (in Ref. 7; AAH61255)"
FT /evidence="ECO:0000305"
FT CONFLICT 152
FT /note="N -> K (in Ref. 1; AAB09469)"
FT /evidence="ECO:0000305"
FT HELIX 107..116
FT /evidence="ECO:0007829|PDB:6KN1"
FT HELIX 118..120
FT /evidence="ECO:0007829|PDB:6KN1"
FT TURN 127..129
FT /evidence="ECO:0007829|PDB:6KN1"
FT STRAND 133..138
FT /evidence="ECO:0007829|PDB:6KN1"
FT STRAND 143..145
FT /evidence="ECO:0007829|PDB:6KN1"
FT HELIX 151..164
FT /evidence="ECO:0007829|PDB:6KN1"
FT STRAND 168..174
FT /evidence="ECO:0007829|PDB:6KN1"
FT HELIX 177..188
FT /evidence="ECO:0007829|PDB:6KN1"
FT HELIX 191..193
FT /evidence="ECO:0007829|PDB:6KN1"
FT STRAND 199..205
FT /evidence="ECO:0007829|PDB:6KN1"
FT STRAND 209..213
FT /evidence="ECO:0007829|PDB:6KN1"
FT STRAND 219..221
FT /evidence="ECO:0007829|PDB:6KN1"
FT STRAND 224..226
FT /evidence="ECO:0007829|PDB:6KN1"
FT HELIX 227..234
FT /evidence="ECO:0007829|PDB:6KN1"
FT TURN 236..238
FT /evidence="ECO:0007829|PDB:6KN1"
FT HELIX 240..242
FT /evidence="ECO:0007829|PDB:6KN1"
FT STRAND 247..253
FT /evidence="ECO:0007829|PDB:6KN1"
FT STRAND 255..258
FT /evidence="ECO:0007829|PDB:6KMU"
FT STRAND 260..264
FT /evidence="ECO:0007829|PDB:6KN1"
FT STRAND 282..284
FT /evidence="ECO:0007829|PDB:6KMU"
FT STRAND 288..293
FT /evidence="ECO:0007829|PDB:6KN1"
FT STRAND 295..302
FT /evidence="ECO:0007829|PDB:6KN1"
FT HELIX 305..307
FT /evidence="ECO:0007829|PDB:6KMT"
FT STRAND 309..311
FT /evidence="ECO:0007829|PDB:6KMU"
FT TURN 312..314
FT /evidence="ECO:0007829|PDB:6KMU"
FT HELIX 317..329
FT /evidence="ECO:0007829|PDB:6KN1"
FT TURN 330..332
FT /evidence="ECO:0007829|PDB:6KN1"
FT HELIX 335..345
FT /evidence="ECO:0007829|PDB:6KN1"
FT STRAND 357..361
FT /evidence="ECO:0007829|PDB:6KN1"
SQ SEQUENCE 373 AA; 42742 MW; 110D7AA75E71C2B3 CRC64;
MAENKHPDKP LKVLEQLGKE VLTEYLEKLV QSNVLKLKEE DKQKFNNAER SDKRWVFVDA
MKKKHSKVGE MLLQTFFSVD PGSHHGEANL EMEEPEESLN TLKLCSPEEF TRLCREKTQE
IYPIKEANGR TRKALIICNT EFKHLSLRYG ANFDIIGMKG LLEDLGYDVV VKEELTAEGM
ESEMKDFAAL SEHQTSDSTF LVLMSHGTLH GICGTMHSEK TPDVLQYDTI YQIFNNCHCP
GLRDKPKVII VQACRGGNSG EMWIRESSKP QLCRGVDLPR NMEADAVKLS HVEKDFIAFY
STTPHHLSYR DKTGGSYFIT RLISCFRKHA CSCHLFDIFL KVQQSFEKAS IHSQMPTIDR
ATLTRYFYLF PGN
