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 27-MAR-2024, entry version 204. 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:12065591, 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 FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION. RX PubMed=12065591; DOI=10.1074/jbc.m203941200; RA Benchoua A., Couriaud C., Guegan C., Tartier L., Couvert P., Friocourt G., RA Chelly J., Menissier-de Murcia J., Onteniente B.; RT "Active caspase-8 translocates into the nucleus of apoptotic cells to RT inactivate poly(ADP-ribose) polymerase-2."; RL J. Biol. Chem. 277:34217-34222(2002). RN [7] 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 [8] 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 [9] 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 [10] 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 [11] 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 [12] 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 RC 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 [13] 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 [14] 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 [15] 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 [16] 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 [17] 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 [18] 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 [19] 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 [20] 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; 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 [21] 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 [22] 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 [23] 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 [24] 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:12065591, PubMed:18455983, CC PubMed:30361383, PubMed:30381458, PubMed:31511692, PubMed:31748744, CC PubMed:33397971). Initiator protease that induces extrinsic apoptosis CC by mediating cleavage and activation of effector caspases responsible CC for FAS/CD95-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 FAS/CD95 or TNFRSF1A (PubMed:29440439). The CC resulting aggregate called the death-inducing signaling complex (DISC) CC performs CASP8 proteolytic activation (By similarity). The active CC dimeric enzyme is then liberated from the DISC and free to activate CC downstream apoptotic proteases (By similarity). Proteolytic fragments CC of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely CC retained in the DISC (By similarity). In addition to extrinsic CC apoptosis, also acts as a negative regulator of necroptosis: acts by CC cleaving RIPK1 at 'Asp-325', which is crucial to inhibit RIPK1 kinase CC activity, limiting TNF-induced apoptosis, necroptosis and inflammatory CC response (PubMed:31511692). Also able to initiate pyroptosis by CC mediating cleavage and activation of gasdermin-C and -D (GSDMC and CC GSDMD, respectively): gasdermin cleavage promotes release of the N- CC terminal moiety that binds to membranes and forms pores, triggering CC pyroptosis (PubMed:30361383, PubMed:30381458). Initiates pyroptosis CC 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 and PARP2 (PubMed:12065591). CC {ECO:0000250|UniProtKB:Q14790, ECO:0000269|PubMed:12065591, CC ECO:0000269|PubMed:18455983, ECO:0000269|PubMed:24813849, CC ECO:0000269|PubMed:24813850, ECO:0000269|PubMed:29440439, CC ECO:0000269|PubMed:30361383, ECO:0000269|PubMed:30381458, CC ECO:0000269|PubMed:31511692, ECO:0000269|PubMed:31748744, CC ECO:0000269|PubMed:32971525, ECO:0000269|PubMed:33397971, CC ECO:0000269|PubMed:9654089, 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:12065591, CC ECO:0000269|PubMed:32971525, ECO:0000269|PubMed:9654089, CC 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). Component of the death-induced signaling CC complex (DISC) composed of cell surface receptor FAS/CD95 or TNFRSF1A, CC adapter protein FADD and the CASP8 protease; recruitment of CASP8 to CC the complex is required for processing of CASP8 into the p18 and p10 CC subunits (By similarity). Component of the AIM2 PANoptosome complex, a CC multiprotein complex that drives inflammatory cell death (PANoptosis) CC (PubMed:34471287). Interacts with CFLAR and PEA15 (By similarity). CC Interacts with RFFL and RNF34; negatively regulate CASP8 through CC proteasomal degradation (By similarity). Interacts with TNFAIP8L2 CC (PubMed:18455983). Interacts with CASP8AP2 (PubMed:17245429). Interacts CC with NOL3; decreases CASP8 activity in a mitochondria localization- and CC phosphorylation-dependent manner and this interaction is dissociated by CC calcium (PubMed:15383280). Interacts with UBR2 (By similarity). CC Interacts with RIPK1 (PubMed:31519887). Interacts with stimulated CC TNFRSF10B; this interaction is followed by CASP8 proteolytic cleavage CC and activation (By similarity). {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:0000269|PubMed:12065591}. Nucleus CC {ECO:0000269|PubMed:12065591}. Note=Translocates into the nucleus CC during apoptosis. {ECO:0000269|PubMed:12065591}. 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}. 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; 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 CCDS; CCDS78590.1; -. DR RefSeq; NP_001073595.1; NM_001080126.1. DR RefSeq; NP_001264855.1; NM_001277926.1. DR RefSeq; NP_033942.1; NM_009812.2. DR AlphaFoldDB; O89110; -. DR SMR; O89110; -. DR BioGRID; 198500; 22. 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.ENSMUSP00000140546; -. DR ChEMBL; CHEMBL4630806; -. DR MEROPS; C14.009; -. DR GlyGen; O89110; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; O89110; -. DR PhosphoSitePlus; O89110; -. DR EPD; O89110; -. DR PaxDb; 10090-ENSMUSP00000027189; -. DR PeptideAtlas; O89110; -. DR ProteomicsDB; 279914; -. DR Pumba; O89110; -. DR Antibodypedia; 697; 1645 antibodies from 51 providers. DR DNASU; 12370; -. DR Ensembl; ENSMUST00000027189.15; ENSMUSP00000027189.9; ENSMUSG00000026029.15. DR Ensembl; ENSMUST00000165549.8; ENSMUSP00000127375.2; ENSMUSG00000026029.15. DR GeneID; 12370; -. DR KEGG; mmu:12370; -. DR UCSC; uc007bcs.1; mouse. DR AGR; MGI:1261423; -. 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; WNRIEDG; -. DR OrthoDB; 2873736at2759; -. 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 Reactome; R-MMU-9758274; Regulation of NF-kappa B signaling. DR BioGRID-ORCS; 12370; 19 hits in 83 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 232 other cell types or tissues. DR ExpressionAtlas; O89110; baseline and differential. 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:0005739; C:mitochondrion; HDA: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:0008656; F:cysteine-type endopeptidase activator activity involved in apoptotic process; IDA:MGI. 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: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: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 canonical NF-kappaB signal transduction; 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:0043123; P:positive regulation of canonical NF-kappaB signal transduction; ISO:MGI. DR GO; GO:1900119; P:positive regulation of execution phase of apoptosis; IDA:MGI. DR GO; GO:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; IGI: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:0043525; P:positive regulation of neuron apoptotic process; ISO:MGI. DR GO; GO:0045862; P:positive regulation of proteolysis; ISO:MGI. DR GO; GO:0051604; P:protein maturation; 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 CDD; cd08333; DED_Caspase_8_r1; 1. DR Gene3D; 3.40.50.1460; -; 1. DR Gene3D; 1.10.533.10; Death Domain, Fas; 2. DR InterPro; IPR033170; Caspase-8_DED1. 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; IPR011600; Pept_C14_caspase. DR InterPro; IPR002138; Pept_C14_p10. DR InterPro; IPR001309; Pept_C14_p20. DR InterPro; IPR015917; Pept_C14A. DR PANTHER; PTHR48169:SF5; CASPASE 10; 1. DR PANTHER; PTHR48169; DED DOMAIN-CONTAINING PROTEIN; 1. DR Pfam; PF01335; DED; 2. DR Pfam; PF00656; Peptidase_C14; 1. DR PRINTS; PR00376; IL1BCENZYME. DR SMART; SM00115; CASc; 1. DR SMART; SM00031; DED; 2. DR SUPFAM; SSF52129; Caspase-like; 1. DR SUPFAM; SSF47986; DEATH domain; 2. 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. DR Genevisible; O89110; MM. 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 //