ID CASP8_HUMAN Reviewed; 479 AA.
AC Q14790; O14676; Q14791; Q14792; Q14793; Q14794; Q14795; Q14796;
AC Q15780; Q15806; Q53TT5; Q8TDI1; Q8TDI2; Q8TDI3; Q8TDI4; Q8TDI5;
AC Q96T22; Q9C0K4; Q9UQ81;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 01-MAY-2013, entry version 166.
DE RecName: Full=Caspase-8;
DE Short=CASP-8;
DE EC=3.4.22.61;
DE AltName: Full=Apoptotic cysteine protease;
DE AltName: Full=Apoptotic protease Mch-5;
DE AltName: Full=CAP4;
DE AltName: Full=FADD-homologous ICE/ced-3-like protease;
DE AltName: Full=FADD-like ICE;
DE Short=FLICE;
DE AltName: Full=ICE-like apoptotic protease 5;
DE AltName: Full=MORT1-associated ced-3 homolog;
DE Short=MACH;
DE Contains:
DE RecName: Full=Caspase-8 subunit p18;
DE Contains:
DE RecName: Full=Caspase-8 subunit p10;
DE Flags: Precursor;
GN Name=CASP8; Synonyms=MCH5;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 5; 6; 7 AND 8).
RC TISSUE=B-cell, and Thymus;
RX PubMed=8681376; DOI=10.1016/S0092-8674(00)81265-9;
RA Boldin M.P., Goncharov T.M., Goltsev Y.V., Wallach D.;
RT "Involvement of MACH, a novel MORT1/FADD-interacting protease, in
RT Fas/APO-1- and TNF receptor-induced cell death.";
RL Cell 85:803-815(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=8681377; DOI=10.1016/S0092-8674(00)81266-0;
RA Muzio M., Chinnaiyan A.M., Kischkel F.C., O'Rourke K., Shevchenko A.,
RA Ni J., Scaffidi C., Bretz J.D., Zhang M., Gentz R., Mann M.,
RA Krammer P.H., Peter M.E., Dixit V.M.;
RT "FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited
RT to the CD95 (Fas/APO-1) death-inducing signaling complex.";
RL Cell 85:817-827(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4), AND VARIANT HIS-285.
RC TISSUE=T-cell;
RX PubMed=8755496; DOI=10.1073/pnas.93.15.7464;
RA Fernandes-Alnemri T., Armstrong R.C., Krebs J.F., Srinivasula S.M.,
RA Wang L., Bullrich F., Fritz L.C., Trapani J.A., Tomaselli K.J.,
RA Litwack G., Alnemri E.S.;
RT "In vitro activation of CPP32 and Mch3 by Mch4, a novel human
RT apoptotic cysteine protease containing two FADD-like domains.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:7464-7469(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND VARIANT HIS-285.
RX PubMed=9228018; DOI=10.1074/jbc.272.30.18542;
RA Srinivasula S.M., Ahmad M., Ottilie S., Bullrich F., Banks S.,
RA Wang Y., Fernandes-Alnemri T., Croce C.M., Litwack G., Tomaselli K.J.,
RA Armstrong R.C., Alnemri E.S.;
RT "FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates
RT Fas/TNFR1-induced apoptosis.";
RL J. Biol. Chem. 272:18542-18545(1997).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9931493; DOI=10.1016/S0378-1119(98)00565-4;
RA Grenet J., Teitz T., Wei T., Valentine V., Kidd V.J.;
RT "Structure and chromosome localization of the human CASP8 gene.";
RL Gene 226:225-232(1999).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT HIS-285.
RX PubMed=11161814; DOI=10.1006/geno.2000.6392;
RA Hadano S., Yanagisawa Y., Skaug J., Fichter K., Nasir J.,
RA Martindale D., Koop B.F., Scherer S.W., Nicholson D.W., Rouleau G.A.,
RA Ikeda J.-E., Hayden M.R.;
RT "Cloning and characterization of three novel genes, ALS2CR1, ALS2CR2,
RT and ALS2CR3, in the juvenile amyotrophic lateral sclerosis (ALS2)
RT critical region at chromosome 2q33-q34: candidate genes for ALS2.";
RL Genomics 71:200-213(2001).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 7), AND FUNCTION (ISOFORM 7).
RC TISSUE=Leukocyte;
RX PubMed=12010809; DOI=10.1182/blood.V99.11.4070;
RA Himeji D., Horiuchi T., Tsukamoto H., Hayashi K., Watanabe T.,
RA Harada M.;
RT "Characterization of caspase-8L: a novel isoform of caspase-8 that
RT behaves as an inhibitor of the caspase cascade.";
RL Blood 99:4070-4078(2002).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 9), AND INTERACTION OF
RP ISOFORM 9 WITH BCAP31 AT THE ENDOPLASMIC RETICULUM.
RX PubMed=11917123; DOI=10.1073/pnas.072088099;
RA Breckenridge D.G., Nguyen M., Kuppig S., Reth M., Shore G.C.;
RT "The procaspase-8 isoform, procaspase-8L, recruited to the BAP31
RT complex at the endoplasmic reticulum.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:4331-4336(2002).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS THR-219 AND HIS-285.
RG NIEHS SNPs program;
RL Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 7).
RC TISSUE=Leukocyte;
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
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [12]
RP PARTIAL PROTEIN SEQUENCE, AND PROTEOLYTIC PROCESSING.
RX PubMed=8962078; DOI=10.1073/pnas.93.25.14486;
RA Srinivasula S.M., Ahmad M., Fernandes-Alnemri T., Litwack G.,
RA Alnemri E.S.;
RT "Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1
RT protease Mch5 is a CrmA-inhibitable protease that activates multiple
RT Ced-3/ICE-like cysteine proteases.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:14486-14491(1996).
RN [13]
RP FUNCTION.
RX PubMed=9006941; DOI=10.1074/jbc.272.5.2952;
RA Muzio M., Salvesen G.S., Dixit V.M.;
RT "FLICE induced apoptosis in a cell-free system. Cleavage of caspase
RT zymogens.";
RL J. Biol. Chem. 272:2952-2956(1997).
RN [14]
RP PROTEOLYTIC PROCESSING.
RX PubMed=9184224; DOI=10.1093/emboj/16.10.2794;
RA Medema J.P., Scaffidi C., Kischkel F.C., Shevchenko A., Mann M.,
RA Krammer P.H., Peter M.E.;
RT "FLICE is activated by association with the CD95 death-inducing
RT signaling complex (DISC).";
RL EMBO J. 16:2794-2804(1997).
RN [15]
RP CHARACTERIZATION (ISOFORM 7).
RX PubMed=10860845; DOI=10.1006/bbrc.2000.2841;
RA Horiuchi T., Himeji D., Tsukamoto H., Harashima S., Hashimura C.,
RA Hayashi K.;
RT "Dominant expression of a novel splice variant of caspase-8 in human
RT peripheral blood lymphocytes.";
RL Biochem. Biophys. Res. Commun. 272:877-881(2000).
RN [16]
RP INTERACTION WITH BCL2; BCL2L1 AND BCAP31.
RX PubMed=9334338; DOI=10.1083/jcb.139.2.327;
RA Ng F.W.H., Nguyen M., Kwan T., Branton P.E., Nicholson D.W.,
RA Cromlish J.A., Shore G.C.;
RT "p28 Bap31, a Bcl-2/Bcl-XL- and procaspase-8-associated protein in the
RT endoplasmic reticulum.";
RL J. Cell Biol. 139:327-338(1997).
RN [17]
RP INTERACTION WITH PEA15.
RX PubMed=10442631; DOI=10.1038/sj.onc.1202831;
RA Condorelli G., Vigliotta G., Cafieri A., Trencia A., Andalo P.,
RA Oriente F., Miele C., Caruso M., Formisano P., Beguinot F.;
RT "PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-
RT induced apoptosis.";
RL Oncogene 18:4409-4415(1999).
RN [18]
RP INTERACTION WITH HHV-5 PROTEIN UL36.
RX PubMed=11427719; DOI=10.1073/pnas.141108798;
RA Skaletskaya A., Bartle L.M., Chittenden T., McCormick A.L.,
RA Mocarski E.S., Goldmacher V.S.;
RT "A cytomegalovirus-encoded inhibitor of apoptosis that suppresses
RT caspase-8 activation.";
RL Proc. Natl. Acad. Sci. U.S.A. 98:7829-7834(2001).
RN [19]
RP SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S).
RX PubMed=14759258; DOI=10.1186/gb-2004-5-2-r8;
RA Hillman R.T., Green R.E., Brenner S.E.;
RT "An unappreciated role for RNA surveillance.";
RL Genome Biol. 5:R8.1-R8.16(2004).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-334, AND MASS
RP SPECTROMETRY.
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [21]
RP MUTAGENESIS OF ASP-73.
RX PubMed=15592525; DOI=10.1038/sj.onc.1208186;
RA Jun J.-I., Chung C.-W., Lee H.-J., Pyo J.-O., Lee K.N., Kim N.-S.,
RA Kim Y.S., Yoo H.-S., Lee T.-H., Kim E., Jung Y.-K.;
RT "Role of FLASH in caspase-8-mediated activation of NF-kappaB:
RT dominant-negative function of FLASH mutant in NF-kappaB signaling
RT pathway.";
RL Oncogene 24:688-696(2005).
RN [22]
RP PHOSPHORYLATION AT SER-387 BY CDK1.
RX PubMed=20937773; DOI=10.1128/MCB.00731-10;
RA Matthess Y., Raab M., Sanhaji M., Lavrik I.N., Strebhardt K.;
RT "Cdk1/cyclin B1 controls Fas-mediated apoptosis by regulating caspase-
RT 8 activity.";
RL Mol. Cell. Biol. 30:5726-5740(2010).
RN [23]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [24]
RP INTERACTION WITH E.COLI NLEF, CATALYTIC ACTIVITY, FUNCTION, AND ENZYME
RP REGULATION.
RA Blasche S., Moertl M., Steuber H., Siszler G., Nisa S., Schwarz F.,
RA Lavrik I., Gronewold T.M.A., Maskos K., Donnenberg M.S., Ullmann D.,
RA Uetz P., Koegl M.;
RT "The E.coli effector protein NleF is a caspase inhibitor.";
RL PLoS ONE 0:0-0(2013).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS).
RX PubMed=10508784; DOI=10.1016/S0969-2126(99)80179-8;
RA Blanchard H., Kodandapani L., Mittl P.R.E., Di Marco S., Krebs J.F.,
RA Wu J.C., Tomaselli K.J., Gruetter M.G.;
RT "The three-dimensional structure of caspase-8: an initiator enzyme in
RT apoptosis.";
RL Structure 7:1125-1133(1999).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (1.2 ANGSTROMS) OF 211-479, AND SUBUNIT.
RX PubMed=10508785; DOI=10.1016/S0969-2126(99)80180-4;
RA Watt W., Koeplinger K.A., Mildner A.M., Heinrikson R.L.,
RA Tomasselli A.G., Watenpaugh K.D.;
RT "The atomic-resolution structure of human caspase-8, a key activator
RT of apoptosis.";
RL Structure 7:1135-1143(1999).
RN [27]
RP VARIANT CASP8D TRP-248.
RX PubMed=12353035; DOI=10.1038/nature01063;
RA Chun H.J., Zheng L., Ahmad M., Wang J., Speirs C.K., Siegel R.M.,
RA Dale J.K., Puck J., Davis J., Hall C.G., Skoda-Smith S.,
RA Atkinson T.P., Straus S.E., Lenardo M.J.;
RT "Pleiotropic defects in lymphocyte activation caused by caspase-8
RT mutations lead to human immunodeficiency.";
RL Nature 419:395-399(2002).
RN [28]
RP VARIANT HIS-285, AND PROTECTION AGAINST BREAST CANCER.
RX PubMed=15601643; DOI=10.1093/jnci/dji001;
RA MacPherson G., Healey C.S., Teare M.D., Balasubramanian S.P.,
RA Reed M.W.R., Pharoah P.D., Ponder B.A.J., Meuth M.,
RA Bhattacharyya N.P., Cox A.;
RT "Association of a common variant of the CASP8 gene with reduced risk
RT of breast cancer.";
RL J. Natl. Cancer Inst. 96:1866-1869(2004).
RN [29]
RP VARIANT HIS-285, AND PROTECTION AGAINST BREAST CANCER.
RX PubMed=17293864; DOI=10.1038/ng1981;
RG The Kathleen Cunningham foundation consortium for research into
RG familial breast cancer;
RG Breast cancer association consortium;
RA Cox A., Dunning A.M., Garcia-Closas M., Balasubramanian S.,
RA Reed M.W.R., Pooley K.A., Scollen S., Baynes C., Ponder B.A.J.,
RA Chanock S., Lissowska J., Brinton L., Peplonska B., Southey M.C.,
RA Hopper J.L., McCredie M.R.E., Giles G.G., Fletcher O., Johnson N.,
RA dos Santos Silva I., Gibson L., Bojesen S.E., Nordestgaard B.G.,
RA Axelsson C.K., Torres D., Hamann U., Justenhoven C., Brauch H.,
RA Chang-Claude J., Kropp S., Risch A., Wang-Gohrke S., Schuermann P.,
RA Bogdanova N., Doerk T., Fagerholm R., Aaltonen K., Blomqvist C.,
RA Nevanlinna H., Seal S., Renwick A., Stratton M.R., Rahman N.,
RA Sangrajrang S., Hughes D., Odefrey F., Brennan P., Spurdle A.B.,
RA Chenevix-Trench G., Beesley J., Mannermaa A., Hartikainen J.,
RA Kataja V., Kosma V.M., Couch F.J., Olson J.E., Goode E.L., Broeks A.,
RA Schmidt M.K., Hogervorst F.B.L., Van't Veer L.J., Kang D., Yoo K.-Y.,
RA Noh D.-Y., Ahn S.-H., Wedren S., Hall P., Low Y.-L., Liu J.,
RA Milne R.L., Ribas G., Gonzalez-Neira A., Benitez J., Sigurdson A.J.,
RA Stredrick D.L., Alexander B.H., Struewing J.P., Pharoah P.D.P.,
RA Easton D.F.;
RT "A common coding variant in CASP8 is associated with breast cancer
RT risk.";
RL Nat. Genet. 39:352-358(2007).
RN [30]
RP ERRATUM.
RG The Kathleen Cunningham foundation consortium for research into
RG familial breast cancer;
RG Breast cancer association consortium;
RA Cox A., Dunning A.M., Garcia-Closas M., Balasubramanian S.,
RA Reed M.W.R., Pooley K.A., Scollen S., Baynes C., Ponder B.A.J.,
RA Chanock S., Lissowska J., Brinton L., Peplonska B., Southey M.C.,
RA Hopper J.L., McCredie M.R.E., Giles G.G., Fletcher O., Johnson N.,
RA dos Santos Silva I., Gibson L., Bojesen S.E., Nordestgaard B.G.,
RA Axelsson C.K., Torres D., Hamann U., Justenhoven C., Brauch H.,
RA Chang-Claude J., Kropp S., Risch A., Wang-Gohrke S., Schuermann P.,
RA Bogdanova N., Doerk T., Fagerholm R., Aaltonen K., Blomqvist C.,
RA Nevanlinna H., Seal S., Renwick A., Stratton M.R., Rahman N.,
RA Sangrajrang S., Hughes D., Odefrey F., Brennan P., Spurdle A.B.,
RA Chenevix-Trench G., Beesley J., Mannermaa A., Hartikainen J.,
RA Kataja V., Kosma V.M., Couch F.J., Olson J.E., Goode E.L., Broeks A.,
RA Schmidt M.K., Hogervorst F.B.L., Van't Veer L.J., Kang D., Yoo K.-Y.,
RA Noh D.-Y., Ahn S.-H., Wedren S., Hall P., Low Y.-L., Liu J.,
RA Milne R.L., Ribas G., Gonzalez-Neira A., Benitez J., Sigurdson A.J.,
RA Stredrick D.L., Alexander B.H., Struewing J.P., Pharoah P.D.P.,
RA Easton D.F.;
RL Nat. Genet. 39:688-688(2007).
RN [31]
RP INVOLVEMENT IN PROTECTION AGAINST LUNG CANCER.
RX PubMed=17450141; DOI=10.1038/ng2030;
RA Sun T., Gao Y., Tan W., Ma S., Shi Y., Yao J., Guo Y., Yang M.,
RA Zhang X., Zhang Q., Zeng C., Lin D.;
RT "A six-nucleotide insertion-deletion polymorphism in the CASP8
RT promoter is associated with susceptibility to multiple cancers.";
RL Nat. Genet. 39:605-613(2007).
RN [32]
RP VARIANT HIS-285, AND RISK FACTOR FOR CUTANEOUS MELANOMA.
RX PubMed=18563783; DOI=10.1002/humu.20803;
RA Li C., Zhao H., Hu Z., Liu Z., Wang L.-E., Gershenwald J.E.,
RA Prieto V.G., Lee J.E., Duvic M., Grimm E.A., Wei Q.;
RT "Genetic variants and haplotypes of the caspase-8 and caspase-10 genes
RT contribute to susceptibility to cutaneous melanoma.";
RL Hum. Mutat. 29:1443-1451(2008).
CC -!- FUNCTION: Most upstream protease of the activation cascade of
CC caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A
CC induced cell death. Binding to the adapter molecule FADD recruits
CC it to either receptor. The resulting aggregate called death-
CC inducing signaling complex (DISC) performs CASP8 proteolytic
CC activation. The active dimeric enzyme is then liberated from the
CC DISC and free to activate downstream apoptotic proteases.
CC Proteolytic fragments of the N-terminal propeptide (termed CAP3,
CC CAP5 and CAP6) are likely retained in the DISC. Cleaves and
CC activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May
CC participate in the GZMB apoptotic pathways. Cleaves ADPRT.
CC Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC.
CC Likely target for the cowpox virus CRMA death inhibitory protein.
CC Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic
CC site and may interfere with the pro-apoptotic activity of the
CC complex.
CC -!- CATALYTIC ACTIVITY: Strict requirement for Asp at position P1 and
CC has a preferred cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-|-
CC (Gly/Ser/Ala).
CC -!- ENZYME REGULATION: Inhibited by the effector protein NleF that is
CC produced by pathogenic E.coli; this inhibits apoptosis.
CC -!- SUBUNIT: Heterotetramer that consists of two anti-parallel
CC arranged heterodimers, each one formed by a 18 kDa (p18) and a 10
CC kDa (p10) subunit. Interacts with FADD, CFLAR and PEA15. Isoform 9
CC interacts at the endoplasmic reticulum with a complex containing
CC BCAP31, BAP29, BCL2 and/or BCL2L1. Interacts with TNFAIP8L2 (By
CC similarity). Interacts with human cytomegalovirus/HHV-5 protein
CC vICA/UL36; this interaction inhibits CASP8 activation. Interacts
CC with NleF from pathogenic E.coli.
CC -!- INTERACTION:
CC Self; NbExp=3; IntAct=EBI-78060, EBI-78060;
CC P51572:BCAP31; NbExp=3; IntAct=EBI-78060, EBI-77683;
CC Q92851:CASP10; NbExp=5; IntAct=EBI-78060, EBI-495095;
CC Q13618:CUL3; NbExp=6; IntAct=EBI-78060, EBI-456129;
CC Q13158:FADD; NbExp=30; IntAct=EBI-78060, EBI-494804;
CC P25445:FAS; NbExp=12; IntAct=EBI-78060, EBI-494743;
CC Q13418:ILK; NbExp=2; IntAct=EBI-78060, EBI-747644;
CC Q9UDY8:MALT1; NbExp=8; IntAct=EBI-78060, EBI-1047372;
CC O60936:NOL3; NbExp=3; IntAct=EBI-78060, EBI-740992;
CC Q13546:RIPK1; NbExp=23; IntAct=EBI-78060, EBI-358507;
CC O00220:TNFRSF10A; NbExp=9; IntAct=EBI-78060, EBI-518861;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=9;
CC Name=1; Synonyms=Alpha-1;
CC IsoId=Q14790-1; Sequence=Displayed;
CC Name=2; Synonyms=Alpha-2, MCH5-beta;
CC IsoId=Q14790-2; Sequence=VSP_000810;
CC Name=3; Synonyms=Alpha-3;
CC IsoId=Q14790-3; Sequence=VSP_000813;
CC Name=4; Synonyms=Alpha-4;
CC IsoId=Q14790-4; Sequence=VSP_000809, VSP_000810;
CC Name=5; Synonyms=Beta-1;
CC IsoId=Q14790-5; Sequence=VSP_000814, VSP_000815;
CC Name=6; Synonyms=Beta-2;
CC IsoId=Q14790-6; Sequence=VSP_000811, VSP_000812;
CC Name=7; Synonyms=Beta-3, 8L;
CC IsoId=Q14790-7; Sequence=VSP_000816, VSP_000817;
CC Note=May be produced at very low levels due to a premature stop
CC codon in the mRNA, leading to nonsense-mediated mRNA decay;
CC Name=8; Synonyms=Beta-4;
CC IsoId=Q14790-8; Sequence=VSP_000810, VSP_000816, VSP_000817;
CC Name=9; Synonyms=8L;
CC IsoId=Q14790-9; Sequence=VSP_000808;
CC Note=Ref.8 (AAL87628) sequence is in conflict in position:
CC 14:K->R;
CC -!- TISSUE SPECIFICITY: Isoform 1, isoform 5 and isoform 7 are
CC expressed in a wide variety of tissues. Highest expression in
CC peripheral blood leukocytes, spleen, thymus and liver. Barely
CC detectable in brain, testis and skeletal muscle.
CC -!- DOMAIN: Isoform 9 contains a N-terminal extension that is required
CC for interaction with the BCAP31 complex.
CC -!- PTM: Generation of the subunits requires association with the
CC death-inducing signaling complex (DISC), whereas additional
CC processing is likely due to the autocatalytic activity of the
CC activated protease. GZMB and CASP10 can be involved in these
CC processing events.
CC -!- PTM: Phosphorylation on Ser-387 during mitosis by CDK1 inhibits
CC activation by proteolysis and prevents apoptosis. This
CC phosphorylation occurs in cancer cell lines, as well as in primary
CC breast tissues and lymphocytes.
CC -!- POLYMORPHISM: Genetic variations in CASP8 are associated with
CC reduced risk of lung cancer [MIM:211980] in a population of Han
CC Chinese subjects. Genetic variations are also associated with
CC decreased risk of cancer of various other forms including
CC esophageal, gastric, colorectal, cervical, and breast, acting in
CC an allele dose-dependent manner.
CC -!- DISEASE: Caspase-8 deficiency (CASP8D) [MIM:607271]: Disorder
CC resembling autoimmune lymphoproliferative syndrome (ALPS). It is
CC characterized by lymphadenopathy, splenomegaly, and defective
CC CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It
CC leads to defects in activation of T-lymphocytes, B-lymphocytes,
CC and natural killer cells leading to immunodeficiency characterized
CC by recurrent sinopulmonary and herpes simplex virus infections and
CC poor responses to immunization. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the peptidase C14A family.
CC -!- SIMILARITY: Contains 2 DED (death effector) domains.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA66858.1; Type=Miscellaneous discrepancy;
CC Sequence=CAA66859.1; Type=Miscellaneous discrepancy;
CC -!- WEB RESOURCE: Name=CASP8base; Note=CASP8 mutation db;
CC URL="http://bioinf.uta.fi/CASP8base/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CASP8";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/casp8/";
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DR EMBL; X98172; CAA66853.1; -; mRNA.
DR EMBL; X98173; CAA66854.1; -; mRNA.
DR EMBL; X98174; CAA66855.1; -; mRNA.
DR EMBL; X98175; CAA66856.1; -; mRNA.
DR EMBL; X98176; CAA66857.1; -; mRNA.
DR EMBL; X98177; CAA66858.1; ALT_SEQ; mRNA.
DR EMBL; X98178; CAA66859.1; ALT_SEQ; mRNA.
DR EMBL; U58143; AAC50602.1; -; mRNA.
DR EMBL; U60520; AAC50645.1; -; mRNA.
DR EMBL; AF009620; AAB70913.1; -; mRNA.
DR EMBL; AF102146; AAD24962.1; -; Genomic_DNA.
DR EMBL; AF102139; AAD24962.1; JOINED; Genomic_DNA.
DR EMBL; AF102140; AAD24962.1; JOINED; Genomic_DNA.
DR EMBL; AF102141; AAD24962.1; JOINED; Genomic_DNA.
DR EMBL; AF102142; AAD24962.1; JOINED; Genomic_DNA.
DR EMBL; AF102143; AAD24962.1; JOINED; Genomic_DNA.
DR EMBL; AF102144; AAD24962.1; JOINED; Genomic_DNA.
DR EMBL; AF102145; AAD24962.1; JOINED; Genomic_DNA.
DR EMBL; AB038985; BAB32555.1; -; Genomic_DNA.
DR EMBL; AF380342; AAK57437.1; -; mRNA.
DR EMBL; AF422925; AAL87628.1; -; mRNA.
DR EMBL; AF422926; AAL87629.1; -; mRNA.
DR EMBL; AF422927; AAL87630.1; -; mRNA.
DR EMBL; AF422928; AAL87631.1; -; mRNA.
DR EMBL; AF422929; AAL87632.1; -; mRNA.
DR EMBL; DQ355026; ABC67468.1; -; Genomic_DNA.
DR EMBL; AC007256; AAY24225.1; -; Genomic_DNA.
DR EMBL; BC028223; -; NOT_ANNOTATED_CDS; mRNA.
DR IPI; IPI00000149; -.
DR IPI; IPI00073318; -.
DR IPI; IPI00220721; -.
DR IPI; IPI00220722; -.
DR IPI; IPI00220723; -.
DR IPI; IPI00220724; -.
DR IPI; IPI00220725; -.
DR IPI; IPI00220726; -.
DR IPI; IPI00305242; -.
DR RefSeq; NP_001073593.1; NM_001080124.1.
DR RefSeq; NP_001073594.1; NM_001080125.1.
DR RefSeq; NP_001219.2; NM_001228.4.
DR RefSeq; NP_203519.1; NM_033355.3.
DR RefSeq; NP_203520.1; NM_033356.3.
DR RefSeq; NP_203522.1; NM_033358.3.
DR UniGene; Hs.599762; -.
DR PDB; 1F9E; X-ray; 2.90 A; A/C/E/G/I/K=222-374, B/D/F/H/J/L=390-478.
DR PDB; 1I4E; X-ray; 3.00 A; B=222-479.
DR PDB; 1QDU; X-ray; 2.80 A; A/C/E/G/I/K=222-374, B/D/F/H/J/L=390-477.
DR PDB; 1QTN; X-ray; 1.20 A; A=211-374, B=385-479.
DR PDB; 2C2Z; X-ray; 1.95 A; A=218-374, B=376-479.
DR PDB; 2FUN; X-ray; 3.00 A; B/D=222-479.
DR PDB; 2K7Z; NMR; -; A=217-479.
DR PDB; 2Y1L; X-ray; 1.80 A; A/C=218-374, B/D=376-479.
DR PDB; 3H11; X-ray; 1.90 A; B=217-479.
DR PDB; 3KJN; X-ray; 1.80 A; A=211-374, B=385-479.
DR PDB; 3KJQ; X-ray; 1.80 A; A=211-374, B=385-479.
DR PDBsum; 1F9E; -.
DR PDBsum; 1I4E; -.
DR PDBsum; 1QDU; -.
DR PDBsum; 1QTN; -.
DR PDBsum; 2C2Z; -.
DR PDBsum; 2FUN; -.
DR PDBsum; 2K7Z; -.
DR PDBsum; 2Y1L; -.
DR PDBsum; 3H11; -.
DR PDBsum; 3KJN; -.
DR PDBsum; 3KJQ; -.
DR ProteinModelPortal; Q14790; -.
DR DIP; DIP-30915N; -.
DR IntAct; Q14790; 49.
DR MINT; MINT-91645; -.
DR MEROPS; C14.009; -.
DR PhosphoSite; Q14790; -.
DR DMDM; 2493531; -.
DR PaxDb; Q14790; -.
DR PRIDE; Q14790; -.
DR DNASU; 841; -.
DR Ensembl; ENST00000264274; ENSP00000264274; ENSG00000064012.
DR Ensembl; ENST00000264275; ENSP00000264275; ENSG00000064012.
DR Ensembl; ENST00000323492; ENSP00000325722; ENSG00000064012.
DR Ensembl; ENST00000358485; ENSP00000351273; ENSG00000064012.
DR Ensembl; ENST00000392258; ENSP00000376087; ENSG00000064012.
DR Ensembl; ENST00000392259; ENSP00000376088; ENSG00000064012.
DR Ensembl; ENST00000392263; ENSP00000376091; ENSG00000064012.
DR Ensembl; ENST00000392266; ENSP00000376094; ENSG00000064012.
DR Ensembl; ENST00000432109; ENSP00000412523; ENSG00000064012.
DR GeneID; 841; -.
DR KEGG; hsa:841; -.
DR UCSC; uc002uxo.1; human.
DR UCSC; uc002uxp.1; human.
DR UCSC; uc002uxq.1; human.
DR UCSC; uc002uxr.1; human.
DR UCSC; uc002uxt.1; human.
DR UCSC; uc002uxv.1; human.
DR UCSC; uc010fte.1; human.
DR UCSC; uc010ftf.2; human.
DR CTD; 841; -.
DR GeneCards; GC02P202062; -.
DR HGNC; HGNC:1509; CASP8.
DR HPA; CAB002047; -.
DR HPA; HPA001302; -.
DR HPA; HPA005688; -.
DR MIM; 211980; phenotype.
DR MIM; 601763; gene.
DR MIM; 607271; phenotype.
DR neXtProt; NX_Q14790; -.
DR Orphanet; 3261; Autoimmune lymphoproliferative syndrome.
DR Orphanet; 275517; Autoimmune lymphoproliferative syndrome with recurrent infections.
DR PharmGKB; PA26092; -.
DR eggNOG; NOG303276; -.
DR HOVERGEN; HBG050803; -.
DR InParanoid; Q14790; -.
DR KO; K04398; -.
DR OMA; RVMLFQI; -.
DR BRENDA; 3.4.22.61; 2681.
DR Pathway_Interaction_DB; caspase_pathway; Caspase cascade in apoptosis.
DR Pathway_Interaction_DB; ceramidepathway; Ceramide signaling pathway.
DR Pathway_Interaction_DB; ar_pathway; Coregulation of Androgen receptor activity.
DR Pathway_Interaction_DB; faspathway; FAS signaling pathway (CD95).
DR Pathway_Interaction_DB; hivnefpathway; HIV-1 Nef: Negative effector of Fas and TNF-alpha.
DR Pathway_Interaction_DB; avb3_integrin_pathway; Integrins in angiogenesis.
DR Pathway_Interaction_DB; tnfpathway; TNF receptor signaling pathway.
DR Pathway_Interaction_DB; trail_pathway; TRAIL signaling pathway.
DR Reactome; REACT_578; Apoptosis.
DR Reactome; REACT_6900; Immune System.
DR BindingDB; Q14790; -.
DR ChEMBL; CHEMBL3776; -.
DR ChiTaRS; CASP8; human.
DR EvolutionaryTrace; Q14790; -.
DR GenomeRNAi; 841; -.
DR NextBio; 3510; -.
DR PMAP-CutDB; Q14790; -.
DR ArrayExpress; Q14790; -.
DR Bgee; Q14790; -.
DR Genevestigator; Q14790; -.
DR GermOnline; ENSG00000064012; Homo sapiens.
DR GO; GO:0031265; C:CD95 death-inducing signaling complex; IEA:Compara.
DR GO; GO:0044297; C:cell body; IEA:Compara.
DR GO; GO:0005813; C:centrosome; IDA:HPA.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0031264; C:death-inducing signaling complex; IDA:UniProtKB.
DR GO; GO:0045121; C:membrane raft; IEA:Compara.
DR GO; GO:0005741; C:mitochondrial outer membrane; TAS:Reactome.
DR GO; GO:0043005; C:neuron projection; IEA:Compara.
DR GO; GO:0030690; C:Noc1p-Noc2p complex; IEA:Compara.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; TAS:Reactome.
DR GO; GO:0001525; P:angiogenesis; IEA:Compara.
DR GO; GO:0006921; P:cellular component disassembly involved in execution phase of apoptosis; TAS:Reactome.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB.
DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; IDA:UniProtKB.
DR GO; GO:0007507; P:heart development; IEA:Compara.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0030225; P:macrophage differentiation; IEA:Compara.
DR GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB cascade; IMP:UniProtKB.
DR GO; GO:0001841; P:neural tube formation; IEA:Compara.
DR GO; GO:0070423; P:nucleotide-binding oligomerization domain containing signaling pathway; TAS:Reactome.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IMP:UniProtKB.
DR GO; GO:0045651; P:positive regulation of macrophage differentiation; IMP:UniProtKB.
DR GO; GO:0045862; P:positive regulation of proteolysis; IDA:BHF-UCL.
DR GO; GO:0051291; P:protein heterooligomerization; IEA:Compara.
DR GO; GO:0051603; P:proteolysis involved in cellular protein catabolic process; IMP:BHF-UCL.
DR GO; GO:0046677; P:response to antibiotic; IEA:Compara.
DR GO; GO:0032025; P:response to cobalt ion; IEA:Compara.
DR GO; GO:0009409; P:response to cold; IEA:Compara.
DR GO; GO:0032355; P:response to estradiol stimulus; IEA:Compara.
DR GO; GO:0045471; P:response to ethanol; IEA:Compara.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Compara.
DR GO; GO:0034612; P:response to tumor necrosis factor; IMP:BHF-UCL.
DR GO; GO:0019048; P:virus-host interaction; IEA:UniProtKB-KW.
DR Gene3D; 1.10.533.10; -; 2.
DR InterPro; IPR011029; DEATH-like_dom.
DR InterPro; IPR001875; DED.
DR InterPro; IPR011600; Pept_C14_cat.
DR InterPro; IPR001309; Pept_C14_ICE_p20.
DR InterPro; IPR016129; Pept_C14_ICE_p20_AS.
DR InterPro; IPR002138; Pept_C14_p10.
DR InterPro; IPR002398; Pept_C14_p45.
DR InterPro; IPR015917; Pept_C14_p45_core.
DR PANTHER; PTHR10454; PTHR10454; 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; SSF47986; DEATH_like; 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.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Apoptosis; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Disease mutation;
KW Host-virus interaction; Hydrolase; Phosphoprotein; Polymorphism;
KW Protease; Reference proteome; Repeat; Thiol protease; Zymogen.
FT PROPEP 1 216
FT /FTId=PRO_0000004628.
FT CHAIN 217 374 Caspase-8 subunit p18.
FT /FTId=PRO_0000004629.
FT PROPEP 375 384
FT /FTId=PRO_0000004630.
FT CHAIN 385 479 Caspase-8 subunit p10.
FT /FTId=PRO_0000004631.
FT DOMAIN 2 80 DED 1.
FT DOMAIN 100 177 DED 2.
FT ACT_SITE 317 317
FT ACT_SITE 360 360
FT MOD_RES 188 188 Phosphoserine (By similarity).
FT MOD_RES 334 334 Phosphotyrosine.
FT MOD_RES 387 387 Phosphoserine; by CDK1.
FT VAR_SEQ 1 1 M -> MEGGRRARVVIESKRNFFLGAFPTPFPAEHVELGRL
FT GDSETAMVPGKGGADYILLPFKKM (in isoform 9).
FT /FTId=VSP_000808.
FT VAR_SEQ 102 102 R -> RFHFCRMSWAEANSQCQTQSVPFWRRVDHLLIR
FT (in isoform 4).
FT /FTId=VSP_000809.
FT VAR_SEQ 184 267 Missing (in isoform 3).
FT /FTId=VSP_000813.
FT VAR_SEQ 184 220 ERSSSLEGSPDEFSNGEELCGVMTISDSPREQDSESQ ->
FT DFGQSLPNEKQTSGILSDHQQSQFCKSTGESAQTSQH (in
FT isoform 6).
FT /FTId=VSP_000811.
FT VAR_SEQ 184 198 Missing (in isoform 2, isoform 4 and
FT isoform 8).
FT /FTId=VSP_000810.
FT VAR_SEQ 199 235 GEELCGVMTISDSPREQDSESQTLDKVYQMKSKPRGY ->
FT DFGQSLPNEKQTSGILSDHQQSQFCKSTGESAQTSQH (in
FT isoform 5).
FT /FTId=VSP_000814.
FT VAR_SEQ 221 479 Missing (in isoform 6).
FT /FTId=VSP_000812.
FT VAR_SEQ 236 479 Missing (in isoform 5).
FT /FTId=VSP_000815.
FT VAR_SEQ 269 276 ALTTTFEE -> TVEPKREK (in isoform 7 and
FT isoform 8).
FT /FTId=VSP_000816.
FT VAR_SEQ 277 479 Missing (in isoform 7 and isoform 8).
FT /FTId=VSP_000817.
FT VARIANT 219 219 S -> T (in dbSNP:rs35976359).
FT /FTId=VAR_025816.
FT VARIANT 248 248 R -> W (in CASP8D; dbSNP:rs17860424).
FT /FTId=VAR_014204.
FT VARIANT 285 285 D -> H (associated with protection
FT against breast cancer; also associated
FT with a lower risk of cutaneous melanoma;
FT dbSNP:rs1045485).
FT /FTId=VAR_020127.
FT MUTAGEN 73 73 D->A: Abolishes binding to FLASH. Induces
FT NF-kappa-B activation.
FT MUTAGEN 387 387 S->A: Impaired CDK1-mediated
FT phosphorylation and enhanced apoptosis.
FT CONFLICT 294 294 E -> D (in Ref. 5; AAD24962).
FT CONFLICT 331 331 A -> P (in Ref. 2; AAC50602 and 5;
FT AAD24962).
FT CONFLICT 343 344 LK -> FG (in Ref. 8; AAL87631).
FT STRAND 230 232
FT STRAND 235 240
FT HELIX 246 249
FT HELIX 252 254
FT STRAND 255 257
FT HELIX 263 276
FT STRAND 280 286
FT HELIX 289 301
FT STRAND 310 316
FT STRAND 322 324
FT STRAND 326 328
FT STRAND 330 332
FT HELIX 333 337
FT HELIX 338 340
FT TURN 342 344
FT HELIX 346 348
FT STRAND 353 359
FT STRAND 362 364
FT STRAND 377 379
FT STRAND 395 405
FT STRAND 412 414
FT TURN 415 417
FT HELIX 420 432
FT HELIX 433 435
FT HELIX 439 451
FT TURN 456 459
FT STRAND 465 468
FT STRAND 471 473
SQ SEQUENCE 479 AA; 55391 MW; 7A5FEAA6B39B582F CRC64;
MDFSRNLYDI GEQLDSEDLA SLKFLSLDYI PQRKQEPIKD ALMLFQRLQE KRMLEESNLS
FLKELLFRIN RLDLLITYLN TRKEEMEREL QTPGRAQISA YRVMLYQISE EVSRSELRSF
KFLLQEEISK CKLDDDMNLL DIFIEMEKRV ILGEGKLDIL KRVCAQINKS LLKIINDYEE
FSKERSSSLE GSPDEFSNGE ELCGVMTISD SPREQDSESQ TLDKVYQMKS KPRGYCLIIN
NHNFAKAREK VPKLHSIRDR NGTHLDAGAL TTTFEELHFE IKPHDDCTVE QIYEILKIYQ
LMDHSNMDCF ICCILSHGDK GIIYGTDGQE APIYELTSQF TGLKCPSLAG KPKVFFIQAC
QGDNYQKGIP VETDSEEQPY LEMDLSSPQT RYIPDEADFL LGMATVNNCV SYRNPAEGTW
YIQSLCQSLR ERCPRGDDIL TILTEVNYEV SNKDDKKNMG KQMPQPTFTL RKKLVFPSD
//
