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MGP000419

UniProt Annotations

Entry Information
Gene Namecaspase 8, apoptosis-related cysteine peptidase
Protein EntryCASP8_HUMAN
UniProt IDQ14790
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=9; Name=1; Synonyms=Alpha-1; IsoId=Q14790-1; Sequence=Displayed; Name=2; Synonyms=Alpha-2, MCH5-beta; IsoId=Q14790-2; Sequence=VSP_000810; Name=3; Synonyms=Alpha-3; IsoId=Q14790-3; Sequence=VSP_000813; Name=4; Synonyms=Alpha-4; IsoId=Q14790-4; Sequence=VSP_000809, VSP_000810; Name=5; Synonyms=Beta-1; IsoId=Q14790-5; Sequence=VSP_000814, VSP_000815; Name=6; Synonyms=Beta-2; IsoId=Q14790-6; Sequence=VSP_000811, VSP_000812; Name=7; Synonyms=Beta-3, 8L; IsoId=Q14790-7; Sequence=VSP_000816, VSP_000817; Note=May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.; Name=8; Synonyms=Beta-4; IsoId=Q14790-8; Sequence=VSP_000810, VSP_000816, VSP_000817; Name=9; Synonyms=8L; IsoId=Q14790-9; Sequence=VSP_000808; Note=Ref.8 (AAL87628) sequence is in conflict in position: 14:K->R. {ECO:0000305};
Catalytic ActivityStrict requirement for Asp at position P1 and has a preferred cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-|- (Gly/Ser/Ala). {ECO:0000269|Ref.26}.
DiseaseCaspase-8 deficiency (CASP8D) [MIM:607271]: Disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization. {ECO:0000269|PubMed:12353035}. Note=The disease is caused by mutations affecting the gene represented in this entry.
DomainIsoform 9 contains a N-terminal extension that is required for interaction with the BCAP31 complex.
Enzyme RegulationInhibited by the effector protein NleF that is produced by pathogenic E.coli; this inhibits apoptosis. {ECO:0000269|Ref.26}.
FunctionMost upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death- inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein. Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex. {ECO:0000269|PubMed:9006941, ECO:0000269|Ref.26}.
InteractionP51572:BCAP31; NbExp=3; IntAct=EBI-78060, EBI-77683; Q92851:CASP10; NbExp=3; IntAct=EBI-78060, EBI-495095; Q9UKL3:CASP8AP2; NbExp=3; IntAct=EBI-78060, EBI-2339650; O15519:CFLAR; NbExp=9; IntAct=EBI-78060, EBI-514941; O15519-1:CFLAR; NbExp=2; IntAct=EBI-78060, EBI-4567563; Q13618:CUL3; NbExp=6; IntAct=EBI-78060, EBI-456129; Q13158:FADD; NbExp=37; IntAct=EBI-78060, EBI-494804; P25445:FAS; NbExp=14; IntAct=EBI-78060, EBI-494743; P48023:FASLG; NbExp=4; IntAct=EBI-78060, EBI-495538; Q13418:ILK; NbExp=2; IntAct=EBI-78060, EBI-747644; Q9UDY8:MALT1; NbExp=10; IntAct=EBI-78060, EBI-1047372; O60936:NOL3; NbExp=3; IntAct=EBI-78060, EBI-740992; P29350:PTPN6; NbExp=3; IntAct=EBI-78060, EBI-78260; Q13546:RIPK1; NbExp=23; IntAct=EBI-78060, EBI-358507; Q969K3:RNF34; NbExp=3; IntAct=EBI-78060, EBI-2340642; O00220:TNFRSF10A; NbExp=9; IntAct=EBI-78060, EBI-518861;
PolymorphismGenetic variations in CASP8 are associated with reduced risk of lung cancer [MIM:211980] in a population of Han Chinese subjects. Genetic variations are also associated with decreased risk of cancer of various other forms including esophageal, gastric, colorectal, cervical, and breast, acting in an allele dose-dependent manner.
PtmGeneration of the subunits requires association with the death-inducing signaling complex (DISC), whereas additional processing is likely due to the autocatalytic activity of the activated protease. GZMB and CASP10 can be involved in these processing events. {ECO:0000269|PubMed:8962078, ECO:0000269|PubMed:9184224}.
PtmPhosphorylation on Ser-387 during mitosis by CDK1 inhibits activation by proteolysis and prevents apoptosis. This phosphorylation occurs in cancer cell lines, as well as in primary breast tissues and lymphocytes. {ECO:0000269|PubMed:15592455, ECO:0000269|PubMed:20937773}.
Sequence CautionSequence=CAA66858.1; Type=Miscellaneous discrepancy; Evidence={ECO:0000305}; Sequence=CAA66859.1; Type=Miscellaneous discrepancy; Evidence={ECO:0000305};
SimilarityBelongs to the peptidase C14A family. {ECO:0000305}.
SimilarityContains 2 DED (death effector) domains. {ECO:0000255|PROSITE-ProRule:PRU00065}.
Subcellular LocationCytoplasm.
SubunitHeterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (p18) and a 10 kDa (p10) subunit. Interacts with FADD, CFLAR and PEA15. Isoform 9 interacts at the endoplasmic reticulum with a complex containing BCAP31, BAP29, BCL2 and/or BCL2L1. Interacts with TNFAIP8L2 (By similarity). Interacts with CASP8AP2. Interacts with RFFL and RNF34; negatively regulate CASP8 through proteasomal degradation. Interacts with human cytomegalovirus/HHV-5 protein vICA/UL36; this interaction inhibits CASP8 activation. Interacts with NleF from pathogenic E.coli. {ECO:0000250|UniProtKB:O89110, ECO:0000269|PubMed:10442631, ECO:0000269|PubMed:10508785, ECO:0000269|PubMed:11427719, ECO:0000269|PubMed:11917123, ECO:0000269|PubMed:15069192, ECO:0000269|PubMed:17245429, ECO:0000269|PubMed:9334338, ECO:0000269|Ref.26}.
Tissue SpecificityIsoform 1, isoform 5 and isoform 7 are expressed in a wide variety of tissues. Highest expression in peripheral blood leukocytes, spleen, thymus and liver. Barely detectable in brain, testis and skeletal muscle.
Web ResourceName=CASP8base; Note=CASP8 mutation db; URL="http://structure.bmc.lu.se/idbase/CASP8base/";
Web ResourceName=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/casp8/";
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