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Details on Person UniProt:Q14790-4 CASP8
| Class:Id | ReferenceIsoform:148674 |
|---|---|
| _chainChangeLog | propeptide:1-216 added on Fri February 6 2015;chain:217-374 added on Fri February 6 2015;propeptide:375-384 added on Fri February 6 2015;chain:385-479 added on Fri February 6 2015 |
| _displayName | UniProt:Q14790-4 CASP8 |
| _timestamp | 2026-02-20 22:07:32 |
| chain | propeptide:1-216 chain:217-374 propeptide:375-384 chain:385-479 |
| checksum | 7A5FEAA6B39B582F |
| comment | FUNCTION Thiol protease that plays a key role in programmed cell death by acting as a molecular switch for apoptosis, necroptosis and pyroptosis, and is required to prevent tissue damage during embryonic development and adulthood (PubMed:23516580, PubMed:35338844, PubMed:35446120, PubMed:8681376, PubMed:8681377, PubMed:8962078, PubMed:9006941, PubMed:9184224). Initiator protease that induces extrinsic apoptosis by mediating cleavage and activation of effector caspases responsible for FAS/CD95-mediated and TNFRSF1A-induced cell death (PubMed:23516580, PubMed:35338844, PubMed:35446120, PubMed:8681376, PubMed:8681377, PubMed:8962078, PubMed:9006941, PubMed:9184224). Cleaves and activates effector caspases CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10 (PubMed:16916640, PubMed:8962078, PubMed:9006941). Binding to the adapter molecule FADD recruits it to either receptor FAS/TNFRSF6 or TNFRSF1A (PubMed:8681376, PubMed:8681377). The resulting aggregate called the death-inducing signaling complex (DISC) performs CASP8 proteolytic activation (PubMed:9184224). The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases (PubMed:9184224). Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC (PubMed:9184224). Also cleaves and activates BID, thereby promoting cytochrome C release from mitochrondria (By similarity). In addition to extrinsic apoptosis, also acts as a negative regulator of necroptosis: acts by cleaving RIPK1 at 'Asp-324', which is crucial to inhibit RIPK1 kinase activity, limiting TNF-induced apoptosis, necroptosis and inflammatory response (PubMed:31827280, PubMed:31827281). Also able to initiate pyroptosis by mediating cleavage and activation of gasdermin-C and -D (GSDMC and GSDMD, respectively): gasdermin cleavage promotes release of the N-terminal moiety that binds to membranes and forms pores, triggering pyroptosis (PubMed:32929201, PubMed:34012073). Initiates pyroptosis following inactivation of MAP3K7/TAK1 (By similarity). Also acts as a regulator of innate immunity by mediating cleavage and inactivation of N4BP1 downstream of TLR3 or TLR4, thereby promoting cytokine production (By similarity). May participate in the Granzyme B (GZMB) cell death pathways (PubMed:8755496). Cleaves PARP1 and PARP2 (PubMed:8681376). Independent of its protease activity, promotes cell migration following phosphorylation at Tyr-380 (PubMed:18216014, PubMed:27109099).FUNCTION Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex.FUNCTION Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex.FUNCTION Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex (Probable). Acts as an inhibitor of the caspase cascade (PubMed:12010809).FUNCTION Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex.CATALYTIC ACTIVITY Strict requirement for Asp at position P1 and has a preferred cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-|-(Gly/Ser/Ala).ACTIVITY REGULATION CASP8 activity is restricted by RIPK1 (By similarity). Inhibited by the effector protein NleF that is produced by pathogenic E.coli; this inhibits apoptosis (PubMed:23516580).SUBUNIT Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (p18) and a 10 kDa (p10) subunit (PubMed:10508784). Component of the death-induced signaling complex (DISC) composed of cell surface receptor FAS/CD95 or TNFRSF1A, adapter protein FADD and the CASP8 protease; recruitment of CASP8 to the complex is required for processing of CASP8 into the p18 and p10 subunits (PubMed:8681376, PubMed:8681377, PubMed:9184224). Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis) (By similarity). Interacts with CFLAR and PEA15 (PubMed:10442631). Interacts with TNFAIP8L2 (By similarity). Interacts with CASP8AP2 (PubMed:16378960). Interacts with RFFL and RNF34; negatively regulate CASP8 through proteasomal degradation (PubMed:15069192). Interacts with NOL3; decreases CASP8 activity in a mitochondria localization- and phosphorylation-dependent manner and this interaction is dissociated by calcium (PubMed:15509781). Interacts with UBR2ca (PubMed:28602583). Interacts with RIPK1 (By similarity). Interacts with stimulated TNFRSF10B; this interaction is followed by CASP8 proteolytic cleavage and activation (PubMed:18846110). Interacts (phosphorylated on Tyr-380) with PIK3R1 (PubMed:27109099).SUBUNIT Interacts at the endoplasmic reticulum with a complex containing BCAP31, BAP29, BCL2 and/or BCL2L1.SUBUNIT (Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein vICA/UL36; this interaction inhibits CASP8 activation.SUBUNIT (Microbial infection) Interacts with NleF from pathogenic E.coli.SUBUNIT (Microbial infection) Interacts with molluscum contagiosum virus protein MC160.SUBUNIT (Microbial infection) Interacts (via RIP homotypic interaction motif) with herpes simplex virus 1/HHV-1 protein RIR1/ICP6 (via RIP homotypic interaction motif); this interaction prevents necroptosis activation.SUBUNIT (Microbial infection) Interacts (via RIP homotypic interaction motif) with herpes simplex virus 2/HHV-2 protein RIR1/ICP10 (via RIP homotypic interaction motif); this interaction prevents necroptosis activation.INTERACTION Recruitment to lamellipodia of migrating cells is enhanced by phosphorylation at Tyr-380.ALTERNATIVE PRODUCTS Isoform 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.DOMAIN The catalytic domain is sufficient for recruitment to lamellipodia but catalytic activity is not necessary.DOMAIN Contains a N-terminal extension that is required for interaction with the BCAP31 complex.PTM Generation of the p10 and p18 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.PTM Phosphorylation on Ser-387 during mitosis by CDK1 inhibits activation by proteolysis and prevents apoptosis (PubMed:20937773). Phosphorylation on Tyr-380 by SRC is mediated by interaction with the SRC SH2 domain and does not affect dimerization or recruitment to the death-inducing signaling complex (DISC) but negatively regulates DISC-mediated processing and activation of CASP8, down-regulating its proapoptotic function (PubMed:16619028, PubMed:27109099). Phosphorylation on Tyr-380 also enhances localization to lamellipodia in migrating cells (PubMed:18216014).PTM (Microbial infection) ADP-riboxanation by C.violaceum CopC blocks CASP8 processing, preventing CASP8 activation and ability to mediate extrinsic apoptosis.PTM (Microbial infection) Proteolytically cleaved by the cowpox virus CRMA death inhibitory protein.POLYMORPHISM Genetic 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.DISEASE The disease is caused by variants affecting the gene represented in this entry.MISCELLANEOUS May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.SIMILARITY Belongs to the peptidase C14A family.SEQUENCE CAUTION CASP8 mutation db |
| description | recommendedName: fullName evidence="46"Caspase-8 shortName evidence="46"CASP-8 ecNumber evidence="26 32 33 39"3.4.22.61 alternativeName: Apoptotic cysteine protease alternativeName: fullName evidence="51"Apoptotic protease Mch-5 alternativeName: CAP4 alternativeName: fullName evidence="49"FADD-homologous ICE/ced-3-like protease alternativeName: fullName evidence="49"FADD-like ICE shortName evidence="49"FLICE alternativeName: ICE-like apoptotic protease 5 alternativeName: fullName evidence="48"MORT1-associated ced-3 homolog shortName evidence="48"MACH component recommendedName: fullName evidence="51"Caspase-8 subunit p18 /component component recommendedName: fullName evidence="51"Caspase-8 subunit p10 /component |
| geneName | CASP8 MCH5 |
| identifier | Q14790 |
| isoformParent | |
| isSequenceChanged | FALSE |
| keyword | 3D-structure Acetylation Alternative splicing Apoptosis Cell projection Cytoplasm Direct protein sequencing Disease variant Host-virus interaction Hydrolase Nucleus Phosphoprotein Protease Proteomics identification Reference proteome Repeat Thiol protease Zymogen |
| modified | [InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9862192] Weiser, Joel, 2024-02-26 [InstanceEdit:9909836] Weiser, Joel, 2024-05-14 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9983091] Weiser, Joel, 2026-02-20 |
| name | CASP8 |
| referenceDatabase | [ReferenceDatabase:2] UniProt |
| referenceGene | [ReferenceDNASequence:8962508] ENSEMBL:ENSG00000064012 CASP8 [Homo sapiens] |
| secondaryIdentifier | CASP8_HUMAN O14676 Q14791 Q14792 Q14793 Q14794 Q14795 Q14796 Q15780 Q15806 Q53TT5 Q8TDI1 Q8TDI2 Q8TDI3 Q8TDI4 Q8TDI5 Q96T22 Q9C0K4 Q9UQ81 |
| sequenceLength | 479 |
| species | [Species:48887] Homo sapiens |
| variantIdentifier | Q14790-4 |
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No pathways have been reviewed or authored by UniProt:Q14790-4 CASP8 (148674)
