CASP8_MOUSE
ID CASP8_MOUSE Reviewed; 480 AA.
AC O89110; O35669;
DT 15-NOV-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1998, sequence version 1.
DT 03-AUG-2022, entry version 195.
DE RecName: Full=Caspase-8 {ECO:0000303|PubMed:9654089, ECO:0000303|PubMed:9837723};
DE Short=CASP-8 {ECO:0000303|PubMed:9654089, ECO:0000303|PubMed:9837723};
DE EC=3.4.22.61 {ECO:0000269|PubMed:32971525, ECO:0000269|PubMed:9654089, ECO:0000269|PubMed:9837723};
DE Contains:
DE RecName: Full=Caspase-8 subunit p18 {ECO:0000303|PubMed:9837723};
DE Contains:
DE RecName: Full=Caspase-8 subunit p10 {ECO:0000303|PubMed:9837723};
DE Flags: Precursor;
GN Name=Casp8 {ECO:0000303|PubMed:9654089, ECO:0000303|PubMed:9837723,
GN ECO:0000312|MGI:MGI:1261423};
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 [GENOMIC DNA / MRNA], FUNCTION, TISSUE SPECIFICITY, AND
RP DEVELOPMENTAL STAGE.
RC STRAIN=129/SvJ;
RX PubMed=9654089; DOI=10.1046/j.1432-1327.1998.2530399.x;
RA Sakamaki K., Tsukumo S., Yonehara S.;
RT "Molecular cloning and characterization of mouse caspase-8.";
RL Eur. J. Biochem. 253:399-405(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, TISSUE
RP SPECIFICITY, DEVELOPMENTAL STAGE, AND ACTIVITY REGULATION.
RX PubMed=9837723; DOI=10.1006/jmbi.1998.2226;
RA Van de Craen M., Van Loo G., Declercq W., Schotte P., van den Brande I.,
RA Mandruzzato S., van der Bruggen P., Fiers W., Vandenabeele P.;
RT "Molecular cloning and identification of murine caspase-8.";
RL J. Mol. Biol. 284:1017-1026(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N; TISSUE=Colon, and Mammary gland;
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 [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 57-476.
RA Kioschis P., Kischkel F., Poustka A., Krammer P.;
RL Submitted (JUL-1997) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP DISRUPTION PHENOTYPE.
RX PubMed=9729047; DOI=10.1016/s1074-7613(00)80609-3;
RA Varfolomeev E.E., Schuchmann M., Luria V., Chiannilkulchai N.,
RA Beckmann J.S., Mett I.L., Rebrikov D., Brodianski V.M., Kemper O.C.,
RA Kollet O., Lapidot T., Soffer D., Sobe T., Avraham K.B., Goncharov T.,
RA Holtmann H., Lonai P., Wallach D.;
RT "Targeted disruption of the mouse Caspase 8 gene ablates cell death
RT induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal
RT prenatally.";
RL Immunity 9:267-276(1998).
RN [6]
RP INTERACTION WITH NOL3.
RX PubMed=15383280; DOI=10.1016/j.molcel.2004.08.020;
RA Nam Y.J., Mani K., Ashton A.W., Peng C.F., Krishnamurthy B., Hayakawa Y.,
RA Lee P., Korsmeyer S.J., Kitsis R.N.;
RT "Inhibition of both the extrinsic and intrinsic death pathways through
RT nonhomotypic death-fold interactions.";
RL Mol. Cell 15:901-912(2004).
RN [7]
RP INTERACTION WITH CASP8AP2.
RX PubMed=17245429; DOI=10.1038/sj.emboj.7601504;
RA Milovic-Holm K., Krieghoff E., Jensen K., Will H., Hofmann T.G.;
RT "FLASH links the CD95 signaling pathway to the cell nucleus and nuclear
RT bodies.";
RL EMBO J. 26:391-401(2007).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-188 AND SER-213, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=17242355; DOI=10.1073/pnas.0609836104;
RA Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.;
RT "Large-scale phosphorylation analysis of mouse liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007).
RN [9]
RP INTERACTION WITH TNFAIP8L2.
RX PubMed=18455983; DOI=10.1016/j.cell.2008.03.026;
RA Sun H., Gong S., Carmody R.J., Hilliard A., Li L., Sun J., Kong L., Xu L.,
RA Hilliard B., Hu S., Shen H., Yang X., Chen Y.H.;
RT "TIPE2, a negative regulator of innate and adaptive immunity that maintains
RT immune homeostasis.";
RL Cell 133:415-426(2008).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-188, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic fibroblast;
RX PubMed=19131326; DOI=10.1074/mcp.m800451-mcp200;
RA Sweet S.M., Bailey C.M., Cunningham D.L., Heath J.K., Cooper H.J.;
RT "Large scale localization of protein phosphorylation by use of electron
RT capture dissociation mass spectrometry.";
RL Mol. Cell. Proteomics 8:904-912(2009).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-188 AND SER-213, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, Kidney, Liver, Lung, Pancreas, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-226, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic fibroblast;
RX PubMed=23806337; DOI=10.1016/j.molcel.2013.06.001;
RA Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y.,
RA Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.;
RT "SIRT5-mediated lysine desuccinylation impacts diverse metabolic
RT pathways.";
RL Mol. Cell 50:919-930(2013).
RN [13]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=24813849; DOI=10.1016/j.cell.2014.04.019;
RA Rickard J.A., O'Donnell J.A., Evans J.M., Lalaoui N., Poh A.R., Rogers T.,
RA Vince J.E., Lawlor K.E., Ninnis R.L., Anderton H., Hall C., Spall S.K.,
RA Phesse T.J., Abud H.E., Cengia L.H., Corbin J., Mifsud S., Di Rago L.,
RA Metcalf D., Ernst M., Dewson G., Roberts A.W., Alexander W.S., Murphy J.M.,
RA Ekert P.G., Masters S.L., Vaux D.L., Croker B.A., Gerlic M., Silke J.;
RT "RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency
RT hematopoiesis.";
RL Cell 157:1175-1188(2014).
RN [14]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=24813850; DOI=10.1016/j.cell.2014.04.018;
RA Dillon C.P., Weinlich R., Rodriguez D.A., Cripps J.G., Quarato G.,
RA Gurung P., Verbist K.C., Brewer T.L., Llambi F., Gong Y.N., Janke L.J.,
RA Kelliher M.A., Kanneganti T.D., Green D.R.;
RT "RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3.";
RL Cell 157:1189-1202(2014).
RN [15]
RP FUNCTION, AND INTERACTION WITH FADD.
RX PubMed=29440439; DOI=10.1073/pnas.1722013115;
RA Meng H., Liu Z., Li X., Wang H., Jin T., Wu G., Shan B.,
RA Christofferson D.E., Qi C., Yu Q., Li Y., Yuan J.;
RT "Death-domain dimerization-mediated activation of RIPK1 controls
RT necroptosis and RIPK1-dependent apoptosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 115:E2001-E2009(2018).
RN [16]
RP INTERACTION WITH RIPK1.
RX PubMed=31519887; DOI=10.1038/s41467-019-12033-8;
RA Tang Y., Tu H., Zhang J., Zhao X., Wang Y., Qin J., Lin X.;
RT "K63-linked ubiquitination regulates RIPK1 kinase activity to prevent cell
RT death during embryogenesis and inflammation.";
RL Nat. Commun. 10:4157-4157(2019).
RN [17]
RP FUNCTION.
RX PubMed=30381458; DOI=10.1073/pnas.1809548115;
RA Sarhan J., Liu B.C., Muendlein H.I., Li P., Nilson R., Tang A.Y.,
RA Rongvaux A., Bunnell S.C., Shao F., Green D.R., Poltorak A.;
RT "Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during
RT Yersinia infection.";
RL Proc. Natl. Acad. Sci. U.S.A. 115:E10888-E10897(2018).
RN [18]
RP FUNCTION.
RX PubMed=30361383; DOI=10.1126/science.aau2818;
RA Orning P., Weng D., Starheim K., Ratner D., Best Z., Lee B., Brooks A.,
RA Xia S., Wu H., Kelliher M.A., Berger S.B., Gough P.J., Bertin J.,
RA Proulx M.M., Goguen J.D., Kayagaki N., Fitzgerald K.A., Lien E.;
RT "Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of
RT gasdermin D and cell death.";
RL Science 362:1064-1069(2018).
RN [19]
RP FUNCTION, MUTAGENESIS OF ASP-212; ASP-218; ASP-225; CYS-362 AND ASP-387,
RP PROTEOLYTIC PROCESSING, SITE, AND ACTIVE SITE.
RX PubMed=31511692; DOI=10.1016/j.immuni.2013.06.018;
RA Newton K., Wickliffe K.E., Dugger D.L., Maltzman A., Roose-Girma M.,
RA Dohse M., Komuves L., Webster J.D., Dixit V.M.;
RT "Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and
RT necroptosis.";
RL Nature 574:428-431(2019).
RN [20]
RP FUNCTION, MUTAGENESIS OF CYS-362, AND ACTIVE SITE.
RX PubMed=31748744; DOI=10.1038/s41586-019-1770-6;
RA Fritsch M., Guenther S.D., Schwarzer R., Albert M.C., Schorn F.,
RA Werthenbach J.P., Schiffmann L.M., Stair N., Stocks H., Seeger J.M.,
RA Lamkanfi M., Kroenke M., Pasparakis M., Kashkar H.;
RT "Caspase-8 is the molecular switch for apoptosis, necroptosis and
RT pyroptosis.";
RL Nature 575:683-687(2019).
RN [21]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=32971525; DOI=10.1038/s41586-020-2796-5;
RA Gitlin A.D., Heger K., Schubert A.F., Reja R., Yan D., Pham V.C., Suto E.,
RA Zhang J., Kwon Y.C., Freund E.C., Kang J., Pham A., Caothien R.,
RA Bacarro N., Hinkle T., Xu M., McKenzie B.S., Haley B., Lee W.P., Lill J.R.,
RA Roose-Girma M., Dohse M., Webster J.D., Newton K., Dixit V.M.;
RT "Integration of innate immune signaling by caspase-8 cleavage of N4BP1.";
RL Nature 587:275-280(2020).
RN [22]
RP IDENTIFICATION IN THE AIM2 PANOPTOSOME COMPLEX.
RX PubMed=34471287; DOI=10.1038/s41586-021-03875-8;
RA Lee S., Karki R., Wang Y., Nguyen L.N., Kalathur R.C., Kanneganti T.D.;
RT "AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host
RT defence.";
RL Nature 597:415-419(2021).
RN [23]
RP FUNCTION.
RX PubMed=33397971; DOI=10.1038/s41467-020-20357-z;
RA Muendlein H.I., Connolly W.M., Magri Z., Smirnova I., Ilyukha V.,
RA Gautam A., Degterev A., Poltorak A.;
RT "ZBP1 promotes LPS-induced cell death and IL-1beta release via RHIM-
RT mediated interactions with RIPK1.";
RL Nat. Commun. 12:86-86(2021).
CC -!- FUNCTION: Thiol protease that plays a key role in programmed cell death
CC by acting as a molecular switch for apoptosis, necroptosis and
CC pyroptosis, and is required to prevent tissue damage during embryonic
CC development and adulthood (PubMed:18455983, PubMed:30361383,
CC PubMed:30381458, PubMed:31511692, PubMed:31748744, PubMed:33397971).
CC Initiator protease that induces extrinsic apoptosis by mediating
CC cleavage and activation of effector caspases responsible for the
CC TNFRSF6/FAS mediated and TNFRSF1A induced cell death (PubMed:9654089,
CC PubMed:9837723, PubMed:24813849, PubMed:24813850). Cleaves and
CC activates effector caspases CASP3, CASP4, CASP6, CASP7, CASP9 and
CC CASP10 (By similarity). Binding to the adapter molecule FADD recruits
CC it to either receptor TNFRSF6/FAS mediated or TNFRSF1A
CC (PubMed:29440439). The resulting aggregate called death-inducing
CC signaling complex (DISC) performs CASP8 proteolytic activation (By
CC similarity). The active dimeric enzyme is then liberated from the DISC
CC and free to activate downstream apoptotic proteases (By similarity).
CC Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5
CC and CAP6) are likely retained in the DISC (By similarity). In addition
CC to extrinsic apoptosis, also acts as a negative regulator of
CC necroptosis: acts by cleaving RIPK1 at 'Asp-325', which is crucial to
CC inhibit RIPK1 kinase activity, limiting TNF-induced apoptosis,
CC necroptosis and inflammatory response (PubMed:31511692). Also able to
CC initiate pyroptosis by mediating cleavage and activation of gasdermin-D
CC (GSDMD): GSDMD cleavage promoting release of the N-terminal moiety
CC (Gasdermin-D, N-terminal) that binds to membranes and forms pores,
CC triggering pyroptosis (PubMed:30361383, PubMed:30381458). Initiates
CC pyroptosis following inactivation of MAP3K7/TAK1 (PubMed:30361383,
CC PubMed:30381458). Also acts as a regulator of innate immunity by
CC mediating cleavage and inactivation of N4BP1 downstream of TLR3 or
CC TLR4, thereby promoting cytokine production (PubMed:32971525). May
CC participate in the Granzyme B (GZMB) cell death pathways (By
CC similarity). Cleaves PARP1 (By similarity).
CC {ECO:0000250|UniProtKB:Q14790, ECO:0000269|PubMed:18455983,
CC ECO:0000269|PubMed:24813849, ECO:0000269|PubMed:24813850,
CC ECO:0000269|PubMed:29440439, ECO:0000269|PubMed:30361383,
CC ECO:0000269|PubMed:30381458, ECO:0000269|PubMed:31511692,
CC ECO:0000269|PubMed:31748744, ECO:0000269|PubMed:32971525,
CC ECO:0000269|PubMed:33397971, ECO:0000269|PubMed:9654089,
CC ECO:0000269|PubMed:9837723}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Strict requirement for Asp at position P1 and has a preferred
CC cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-|-(Gly/Ser/Ala).;
CC EC=3.4.22.61; Evidence={ECO:0000269|PubMed:32971525,
CC ECO:0000269|PubMed:9654089, ECO:0000269|PubMed:9837723};
CC -!- ACTIVITY REGULATION: CASP8 activity is restricted by RIPK1.
CC {ECO:0000269|PubMed:24813849, ECO:0000269|PubMed:24813850}.
CC -!- ACTIVITY REGULATION: (Microbial infection) Inhibited by baculovirus p35
CC protein P35. {ECO:0000269|PubMed:9837723}.
CC -!- SUBUNIT: Heterotetramer that consists of two anti-parallel arranged
CC heterodimers, each one formed by a 18 kDa (p18) and a 10 kDa (p10)
CC subunit (By similarity). Interacts with CFLAR and PEA15 (By
CC similarity). Interacts with RFFL and RNF34; negatively regulate CASP8
CC through proteasomal degradation (By similarity). Interacts with
CC TNFAIP8L2 (PubMed:18455983). Interacts with CASP8AP2 (PubMed:17245429).
CC Interacts with NOL3; decreases CASP8 activity in a mitochondria
CC localization- and phosphorylation-dependent manner and this interaction
CC is dissociated by calcium (PubMed:15383280). Interacts with UBR2 (By
CC similarity). Interacts with RIPK1 (PubMed:31519887). Interacts with
CC FADD (PubMed:29440439). Interacts with stimulated TNFRSF10B; this
CC interaction is followed by CASP8 proteolytic cleavage and activation
CC (By similarity). Component of the AIM2 PANoptosome complex, a
CC multiprotein complex that drives inflammatory cell death (PANoptosis)
CC (PubMed:34471287). {ECO:0000250|UniProtKB:Q14790,
CC ECO:0000250|UniProtKB:Q9JHX4, ECO:0000269|PubMed:15383280,
CC ECO:0000269|PubMed:17245429, ECO:0000269|PubMed:18455983,
CC ECO:0000269|PubMed:29440439, ECO:0000269|PubMed:31519887,
CC ECO:0000269|PubMed:34471287}.
CC -!- INTERACTION:
CC O89110; P19091: Ar; NbExp=2; IntAct=EBI-851690, EBI-1776062;
CC O89110; Q61160: Fadd; NbExp=6; IntAct=EBI-851690, EBI-524415;
CC O89110; P25446: Fas; NbExp=3; IntAct=EBI-851690, EBI-296206;
CC O89110; Q9D8Y7: Tnfaip8l2; NbExp=2; IntAct=EBI-851690, EBI-1781612;
CC O89110; P01375: TNF; Xeno; NbExp=2; IntAct=EBI-851690, EBI-359977;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9JHX4}. Nucleus
CC {ECO:0000250|UniProtKB:Q9JHX4}.
CC -!- TISSUE SPECIFICITY: Expressed in a wide variety of tissues. Highest
CC expression in spleen, thymus, lung, liver and kidney. Lower expression
CC in heart, brain, testis and skeletal muscle.
CC {ECO:0000269|PubMed:9654089, ECO:0000269|PubMed:9837723}.
CC -!- DEVELOPMENTAL STAGE: In the embryo, highest expression occurs at day 7.
CC {ECO:0000269|PubMed:9654089, ECO:0000269|PubMed:9837723}.
CC -!- PTM: Generation of the subunits requires association with the death-
CC inducing signaling complex (DISC), whereas additional processing is
CC likely due to the autocatalytic activity of the activated protease
CC (PubMed:31511692). GZMB and CASP10 can be involved in these processing
CC events (By similarity). {ECO:0000250|UniProtKB:Q14790,
CC ECO:0000269|PubMed:31511692}.
CC -!- PTM: (Microbial infection) Proteolytically cleaved by the cowpox virus
CC CRMA death inhibitory protein. {ECO:0000269|PubMed:9837723}.
CC -!- PTM: Phosphorylation on Ser-389 during mitosis by CDK1 inhibits
CC activation by proteolysis and prevents apoptosis. This phosphorylation
CC occurs in cancer cell lines, as well as in primary breast tissues and
CC lymphocytes (By similarity). {ECO:0000250|UniProtKB:Q14790}.
CC -!- DISRUPTION PHENOTYPE: Embryonic lethality at lethality at 10.5 dpc
CC (PubMed:9729047). Embryos display impaired heart muscle development and
CC congested accumulation of erythrocytes (PubMed:9729047). Perinatal
CC lethality observed in Ripk1 knockout mice is rescued in knockout mice
CC lacking both Ripk1 and Casp8; mice however die the first days of
CC postnatal life (PubMed:24813849). Only mice lacking Ripk1, Ripk3 and
CC Casp8 survive past weaning and rescue lethality caused by the absence
CC of Ripk1 (PubMed:24813849, PubMed:24813850).
CC {ECO:0000269|PubMed:24813849, ECO:0000269|PubMed:24813850,
CC ECO:0000269|PubMed:9729047}.
CC -!- SIMILARITY: Belongs to the peptidase C14A family. {ECO:0000305}.
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DR EMBL; AF067841; AAC40132.1; -; Genomic_DNA.
DR EMBL; AF067835; AAC40132.1; JOINED; Genomic_DNA.
DR EMBL; AF067836; AAC40132.1; JOINED; Genomic_DNA.
DR EMBL; AF067837; AAC40132.1; JOINED; Genomic_DNA.
DR EMBL; AF067838; AAC40132.1; JOINED; Genomic_DNA.
DR EMBL; AF067839; AAC40132.1; JOINED; Genomic_DNA.
DR EMBL; AF067840; AAC40132.1; JOINED; Genomic_DNA.
DR EMBL; AF067834; AAC40131.1; -; mRNA.
DR EMBL; AJ007749; CAA07677.1; -; mRNA.
DR EMBL; BC006737; AAH06737.1; -; mRNA.
DR EMBL; BC049955; AAH49955.1; -; mRNA.
DR EMBL; AJ000641; CAA04196.1; -; mRNA.
DR CCDS; CCDS14979.1; -.
DR RefSeq; NP_001073595.1; NM_001080126.1.
DR RefSeq; NP_033942.1; NM_009812.2.
DR AlphaFoldDB; O89110; -.
DR SMR; O89110; -.
DR BioGRID; 198500; 21.
DR ComplexPortal; CPX-1914; Ripoptosome.
DR ComplexPortal; CPX-3663; Caspase-8 complex.
DR DIP; DIP-37435N; -.
DR IntAct; O89110; 8.
DR MINT; O89110; -.
DR STRING; 10090.ENSMUSP00000027189; -.
DR ChEMBL; CHEMBL4630806; -.
DR MEROPS; C14.009; -.
DR iPTMnet; O89110; -.
DR PhosphoSitePlus; O89110; -.
DR EPD; O89110; -.
DR PaxDb; O89110; -.
DR PeptideAtlas; O89110; -.
DR PRIDE; O89110; -.
DR ProteomicsDB; 279914; -.
DR Antibodypedia; 697; 1521 antibodies from 51 providers.
DR DNASU; 12370; -.
DR Ensembl; ENSMUST00000027189; ENSMUSP00000027189; ENSMUSG00000026029.
DR Ensembl; ENSMUST00000165549; ENSMUSP00000127375; ENSMUSG00000026029.
DR GeneID; 12370; -.
DR KEGG; mmu:12370; -.
DR UCSC; uc007bcs.1; mouse.
DR CTD; 841; -.
DR MGI; MGI:1261423; Casp8.
DR VEuPathDB; HostDB:ENSMUSG00000026029; -.
DR eggNOG; KOG3573; Eukaryota.
DR GeneTree; ENSGT00940000160319; -.
DR HOGENOM; CLU_036904_4_2_1; -.
DR InParanoid; O89110; -.
DR OMA; VYRMESK; -.
DR PhylomeDB; O89110; -.
DR TreeFam; TF102023; -.
DR BRENDA; 3.4.22.61; 3474.
DR Reactome; R-MMU-111465; Apoptotic cleavage of cellular proteins.
DR Reactome; R-MMU-140534; Caspase activation via Death Receptors in the presence of ligand.
DR Reactome; R-MMU-168638; NOD1/2 Signaling Pathway.
DR Reactome; R-MMU-2562578; TRIF-mediated programmed cell death.
DR Reactome; R-MMU-264870; Caspase-mediated cleavage of cytoskeletal proteins.
DR Reactome; R-MMU-3371378; Regulation by c-FLIP.
DR Reactome; R-MMU-5218900; CASP8 activity is inhibited.
DR Reactome; R-MMU-5357905; Regulation of TNFR1 signaling.
DR Reactome; R-MMU-5660668; CLEC7A/inflammasome pathway.
DR Reactome; R-MMU-5675482; Regulation of necroptotic cell death.
DR Reactome; R-MMU-69416; Dimerization of procaspase-8.
DR Reactome; R-MMU-75108; Activation, myristolyation of BID and translocation to mitochondria.
DR Reactome; R-MMU-75153; Apoptotic execution phase.
DR Reactome; R-MMU-75157; FasL/ CD95L signaling.
DR Reactome; R-MMU-75158; TRAIL signaling.
DR BioGRID-ORCS; 12370; 19 hits in 78 CRISPR screens.
DR ChiTaRS; Casp8; mouse.
DR PRO; PR:O89110; -.
DR Proteomes; UP000000589; Chromosome 1.
DR RNAct; O89110; protein.
DR Bgee; ENSMUSG00000026029; Expressed in small intestine Peyer's patch and 229 other tissues.
DR ExpressionAtlas; O89110; baseline and differential.
DR Genevisible; O89110; MM.
DR GO; GO:0008303; C:caspase complex; ISO:MGI.
DR GO; GO:0031265; C:CD95 death-inducing signaling complex; ISO:MGI.
DR GO; GO:0044297; C:cell body; ISO:MGI.
DR GO; GO:0005737; C:cytoplasm; IDA:ParkinsonsUK-UCL.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0031264; C:death-inducing signaling complex; ISO:MGI.
DR GO; GO:0045121; C:membrane raft; ISO:MGI.
DR GO; GO:0005739; C:mitochondrion; HDA:MGI.
DR GO; GO:0043005; C:neuron projection; ISO:MGI.
DR GO; GO:0030690; C:Noc1p-Noc2p complex; IMP:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0005886; C:plasma membrane; IDA:ParkinsonsUK-UCL.
DR GO; GO:0032991; C:protein-containing complex; ISO:MGI.
DR GO; GO:0097342; C:ripoptosome; ISS:UniProtKB.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0097153; F:cysteine-type endopeptidase activity involved in apoptotic process; IDA:MGI.
DR GO; GO:0097199; F:cysteine-type endopeptidase activity involved in apoptotic signaling pathway; ISO:MGI.
DR GO; GO:0097200; F:cysteine-type endopeptidase activity involved in execution phase of apoptosis; IBA:GO_Central.
DR GO; GO:0035877; F:death effector domain binding; ISO:MGI.
DR GO; GO:0005123; F:death receptor binding; ISO:MGI.
DR GO; GO:0004175; F:endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0008233; F:peptidase activity; IDA:MGI.
DR GO; GO:0044877; F:protein-containing complex binding; ISO:MGI.
DR GO; GO:0097110; F:scaffold protein binding; ISO:MGI.
DR GO; GO:0005164; F:tumor necrosis factor receptor binding; ISO:MGI.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; ISO:MGI.
DR GO; GO:0097202; P:activation of cysteine-type endopeptidase activity; ISO:MGI.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:MGI.
DR GO; GO:0001525; P:angiogenesis; IMP:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IDA:MGI.
DR GO; GO:0097190; P:apoptotic signaling pathway; IDA:MGI.
DR GO; GO:0048738; P:cardiac muscle tissue development; TAS:UniProtKB.
DR GO; GO:0097194; P:execution phase of apoptosis; IMP:UniProtKB.
DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; IDA:MGI.
DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IMP:MGI.
DR GO; GO:0007507; P:heart development; IMP:UniProtKB.
DR GO; GO:0097284; P:hepatocyte apoptotic process; IMP:MGI.
DR GO; GO:0030225; P:macrophage differentiation; IMP:MGI.
DR GO; GO:0070266; P:necroptotic process; IGI:MGI.
DR GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB signaling; ISO:MGI.
DR GO; GO:0060546; P:negative regulation of necroptotic process; IMP:UniProtKB.
DR GO; GO:0001841; P:neural tube formation; IMP:MGI.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:MGI.
DR GO; GO:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; IGI:MGI.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; ISO:MGI.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; ISO:MGI.
DR GO; GO:0045651; P:positive regulation of macrophage differentiation; ISO:MGI.
DR GO; GO:1901216; P:positive regulation of neuron death; ISO:MGI.
DR GO; GO:0045862; P:positive regulation of proteolysis; ISO:MGI.
DR GO; GO:0016485; P:protein processing; IDA:UniProtKB.
DR GO; GO:0006508; P:proteolysis; ISO:MGI.
DR GO; GO:0051603; P:proteolysis involved in protein catabolic process; IDA:UniProtKB.
DR GO; GO:0070269; P:pyroptosis; IDA:UniProtKB.
DR GO; GO:2001233; P:regulation of apoptotic signaling pathway; IGI:MGI.
DR GO; GO:0001817; P:regulation of cytokine production; IDA:UniProtKB.
DR GO; GO:0045088; P:regulation of innate immune response; IDA:UniProtKB.
DR GO; GO:0070243; P:regulation of thymocyte apoptotic process; IGI:MGI.
DR GO; GO:0045471; P:response to ethanol; ISO:MGI.
DR GO; GO:0034612; P:response to tumor necrosis factor; ISO:MGI.
DR GO; GO:0097264; P:self proteolysis; IMP:UniProtKB.
DR GO; GO:0036462; P:TRAIL-activated apoptotic signaling pathway; ISO:MGI.
DR CDD; cd00032; CASc; 1.
DR Gene3D; 1.10.533.10; -; 2.
DR InterPro; IPR033170; Caspase-8.
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; IPR001875; DED_dom.
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 PANTHER; PTHR10454:SF162; PTHR10454:SF162; 1.
DR Pfam; PF01335; DED; 2.
DR PRINTS; PR00376; IL1BCENZYME.
DR SMART; SM00115; CASc; 1.
DR SMART; SM00031; DED; 2.
DR SUPFAM; SSF47986; SSF47986; 2.
DR SUPFAM; SSF52129; SSF52129; 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 PROSITE; PS50168; DED; 2.
PE 1: Evidence at protein level;
KW Acetylation; Apoptosis; Cytoplasm; Hydrolase; Nucleus; Phosphoprotein;
KW Protease; Reference proteome; Repeat; Thiol protease; Zymogen.
FT PROPEP 1..218
FT /evidence="ECO:0000269|PubMed:31511692"
FT /id="PRO_0000004632"
FT CHAIN 219..376
FT /note="Caspase-8 subunit p18"
FT /evidence="ECO:0000305|PubMed:31511692"
FT /id="PRO_0000004633"
FT PROPEP 377..387
FT /evidence="ECO:0000269|PubMed:31511692"
FT /id="PRO_0000004634"
FT CHAIN 388..480
FT /note="Caspase-8 subunit p10"
FT /evidence="ECO:0000305|PubMed:31511692"
FT /id="PRO_0000004635"
FT DOMAIN 3..80
FT /note="DED 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00065"
FT DOMAIN 101..177
FT /note="DED 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00065"
FT ACT_SITE 319
FT /evidence="ECO:0000250|UniProtKB:Q14790"
FT ACT_SITE 362
FT /evidence="ECO:0000305|PubMed:31511692,
FT ECO:0000305|PubMed:31748744"
FT SITE 218..219
FT /note="Cleavage; by autocatalytic cleavage"
FT /evidence="ECO:0000269|PubMed:31511692"
FT SITE 374..375
FT /note="Cleavage; by CASP6"
FT /evidence="ECO:0000250|UniProtKB:Q14790"
FT SITE 387..388
FT /note="Cleavage; by autocatalytic cleavage"
FT /evidence="ECO:0000269|PubMed:31511692"
FT MOD_RES 188
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17242355,
FT ECO:0007744|PubMed:19131326, ECO:0007744|PubMed:21183079"
FT MOD_RES 213
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17242355,
FT ECO:0007744|PubMed:21183079"
FT MOD_RES 226
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 336
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:Q14790"
FT MOD_RES 389
FT /note="Phosphoserine; by CDK1"
FT /evidence="ECO:0000250|UniProtKB:Q14790"
FT MUTAGEN 212
FT /note="D->A: Loss of autocatalytic cleavage; when
FT associated with A-218; A-225 and A-387."
FT /evidence="ECO:0000269|PubMed:31511692"
FT MUTAGEN 218
FT /note="D->A: Loss of autocatalytic cleavage; when
FT associated with A-212; A-225 and A-387."
FT /evidence="ECO:0000269|PubMed:31511692"
FT MUTAGEN 225
FT /note="D->A: Loss of autocatalytic cleavage; when
FT associated with A-212; A-218 and A-387."
FT /evidence="ECO:0000269|PubMed:31511692"
FT MUTAGEN 362
FT /note="C->A: Loss of kinase ativity. Knockin mice show
FT embryonic lethality caused by endothelial cell necroptosis
FT leading to cardiovascular defects. Mlkl deficiency rescues
FT the cardiovascular phenotype of knockin mice, but causes
FT perinatal lethality caused by induction of pyroptosis."
FT /evidence="ECO:0000269|PubMed:31511692,
FT ECO:0000269|PubMed:31748744"
FT MUTAGEN 387
FT /note="D->A: Loss of autocatalytic cleavage; when
FT associated with A-212; A-218 and A-225."
FT /evidence="ECO:0000269|PubMed:31511692"
FT CONFLICT 68..71
FT /note="HISR -> PHPVG (in Ref. 4; CAA04196)"
FT /evidence="ECO:0000305"
FT CONFLICT 94..99
FT /note="DNAQIS -> RQCPRFL (in Ref. 4; CAA04196)"
FT /evidence="ECO:0000305"
FT CONFLICT 96
FT /note="A -> V (in Ref. 2; CAA07677)"
FT /evidence="ECO:0000305"
FT CONFLICT 103..107
FT /note="VMLFK -> SCSFR (in Ref. 4; CAA04196)"
FT /evidence="ECO:0000305"
FT CONFLICT 475
FT /note="K -> N (in Ref. 4; CAA04196)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 480 AA; 55357 MW; 045268AE3DE5ED4F CRC64;
MDFQSCLYAI AEELGSEDLA ALKFLCLDYI PHKKQETIED AQKLFLRLRE KGMLEEGNLS
FLKELLFHIS RWDLLVNFLD CNREEMVREL RDPDNAQISP YRVMLFKLSE EVSELELRSF
KFLLNNEIPK CKLEDDLSLL EIFVEMEKRT MLAENNLETL KSICDQVNKS LLGKIEDYER
SSTERRMSLE GREELPPSVL DEMSLKMAEL CDSPREQDSE SRTSDKVYQM KNKPRGYCLI
INNHDFSKAR EDITQLRKMK DRKGTDCDKE ALSKTFKELH FEIVSYDDCT ANEIHEILEG
YQSADHKNKD CFICCILSHG DKGVVYGTDG KEASIYDLTS YFTGSKCPSL SGKPKIFFIQ
ACQGSNFQKG VPDEAGFEQQ NHTLEVDSSS HKNYIPDEAD FLLGMATVKN CVSYRDPVNG
TWYIQSLCQS LRERCPQGDD ILSILTGVNY DVSNKDDRRN KGKQMPQPTF TLRKKLFFPP
