Q9JHX4 · CASP8_RAT
- ProteinCaspase-8
- GeneCasp8
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids482 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
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 (By similarity).
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:10197541).
Cleaves and activates effector caspases CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10 (By similarity).
Binding to the adapter molecule FADD recruits it to either receptor FAS/CD95 or TNFRSF1A (PubMed:10197541).
The resulting aggregate called the death-inducing signaling complex (DISC) performs CASP8 proteolytic activation (By similarity).
The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases (By similarity).
Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC (By similarity).
In addition to extrinsic apoptosis, also acts as a negative regulator of necroptosis: acts by cleaving RIPK1 at 'Asp-325', which is crucial to inhibit RIPK1 kinase activity, limiting TNF-induced apoptosis, necroptosis and inflammatory response (By similarity).
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 (By similarity).
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 (By similarity).
Cleaves PARP1 and PARP2 (By similarity).
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:10197541).
Cleaves and activates effector caspases CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10 (By similarity).
Binding to the adapter molecule FADD recruits it to either receptor FAS/CD95 or TNFRSF1A (PubMed:10197541).
The resulting aggregate called the death-inducing signaling complex (DISC) performs CASP8 proteolytic activation (By similarity).
The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases (By similarity).
Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC (By similarity).
In addition to extrinsic apoptosis, also acts as a negative regulator of necroptosis: acts by cleaving RIPK1 at 'Asp-325', which is crucial to inhibit RIPK1 kinase activity, limiting TNF-induced apoptosis, necroptosis and inflammatory response (By similarity).
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 (By similarity).
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 (By similarity).
Cleaves PARP1 and PARP2 (By similarity).
Catalytic activity
Activity regulation
CASP8 activity is restricted by RIPK1.
Features
Showing features for site, active site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Site | 218-219 | Cleavage; by autocatalytic cleavage | ||||
Sequence: ES | ||||||
Active site | 319 | |||||
Sequence: H | ||||||
Active site | 362 | |||||
Sequence: C | ||||||
Site | 376-377 | Cleavage; by CASP6 | ||||
Sequence: ET | ||||||
Site | 388-389 | Cleavage; by autocatalytic cleavage | ||||
Sequence: DS |
GO annotations
Keywords
- Molecular function
- Biological process
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameCaspase-8
- EC number
- Short namesCASP-8
- Cleaved into 2 chains
Gene names
Organism names
- Organism
- Strains
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Rattus
Accessions
- Primary accessionQ9JHX4
Proteomes
Organism-specific databases
PTM/Processing
Features
Showing features for propeptide, modified residue, chain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Propeptide | PRO_0000432425 | 1-218 | ||||
Sequence: MDFHSCLYDIAERLGNEELAALKFLCLDHIPQKKQESINDVLVLFQRLQEEGMLEEDNLSFLKELLFHISRRDLLSRVLKSSPEEMVRELQVLGKAQVSAYRVMLFKLSEDMDKEDLKSFKFLLITEIPKCKLQDNSSLLDIFVEMEKRTILAENNLVTLKSICFRVNRSLLGRIDDYERSSTERRMSTEGGEELPVSVLDEVTIKMQDMWDSPGEQE | ||||||
Modified residue | 188 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 213 | Phosphoserine | ||||
Sequence: S | ||||||
Chain | PRO_0000432426 | 219-378 | Caspase-8 subunit p18 | |||
Sequence: SESLNSDNVYQMKSKPRGYCLIFNNNNFSKAREDIPKLSNMRDRKGTNYDEEALSKTFKELHFEIVSFSDCTASQIHEVLVSYQSKDHKGKDCFICCILSHGDKGIVYGTDGKEASIYELTSYFTGSKCPSLAGKPKIFFIQACQGNNFQKAVPVPDETG | ||||||
Modified residue | 336 | Phosphotyrosine | ||||
Sequence: Y | ||||||
Propeptide | PRO_0000432427 | 379-388 | ||||
Sequence: LEQEHVLEED | ||||||
Chain | PRO_0000432428 | 389-482 | Caspase-8 subunit p10 | |||
Sequence: SSSYKNYIPDEADFLLGMATVKNCVSYRDPTRGTWYIQSLCQSLRERCPRGEDILSILTGVNYDVSNKDNPRNMGKQMPQPIFTLRKKLFFPPN | ||||||
Modified residue | 390 | Phosphoserine; by CDK1 | ||||
Sequence: S |
Post-translational modification
Generation 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 (By similarity).
Phosphorylation on Ser-389 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 (By similarity).
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Gene expression databases
Interaction
Subunit
Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (p18) and a 10 kDa (p10) subunit (By similarity).
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 (By similarity).
Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis) (By similarity).
Interacts with CFLAR and PEA15 (By similarity).
Interacts with RFFL and RNF34; negatively regulate CASP8 through proteasomal degradation (By similarity).
Interacts with TNFAIP8L2 (By similarity).
Interacts with CASP8AP2 (By similarity).
Interacts with NOL3; decreases CASP8 activity in a mitochondria localization- and phosphorylation-dependent manner and this interaction is dissociated by calcium (PubMed:15383280).
Interacts with UBR2 (By similarity).
Interacts with RIPK1 (By similarity).
Interacts with stimulated TNFRSF10B; this interaction is followed by CASP8 proteolytic cleavage and activation (By similarity).
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 (By similarity).
Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis) (By similarity).
Interacts with CFLAR and PEA15 (By similarity).
Interacts with RFFL and RNF34; negatively regulate CASP8 through proteasomal degradation (By similarity).
Interacts with TNFAIP8L2 (By similarity).
Interacts with CASP8AP2 (By similarity).
Interacts with NOL3; decreases CASP8 activity in a mitochondria localization- and phosphorylation-dependent manner and this interaction is dissociated by calcium (PubMed:15383280).
Interacts with UBR2 (By similarity).
Interacts with RIPK1 (By similarity).
Interacts with stimulated TNFRSF10B; this interaction is followed by CASP8 proteolytic cleavage and activation (By similarity).
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | Q9JHX4 | Fadd Q8R2E7 | 2 | EBI-4326675, EBI-4326723 |
Protein-protein interaction databases
Structure
Family & Domains
Features
Showing features for domain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 2-80 | DED 1 | ||||
Sequence: DFHSCLYDIAERLGNEELAALKFLCLDHIPQKKQESINDVLVLFQRLQEEGMLEEDNLSFLKELLFHISRRDLLSRVLK | ||||||
Domain | 100-177 | DED 2 | ||||
Sequence: AYRVMLFKLSEDMDKEDLKSFKFLLITEIPKCKLQDNSSLLDIFVEMEKRTILAENNLVTLKSICFRVNRSLLGRIDD |
Sequence similarities
Belongs to the peptidase C14A family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Sequence processingThe displayed sequence is further processed into a mature form.
- Length482
- Mass (Da)55,339
- Last updated2000-10-01 v1
- Checksum82B4A29330C53264
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF279308 EMBL· GenBank· DDBJ | AAF87778.1 EMBL· GenBank· DDBJ | mRNA | ||
AF288372 EMBL· GenBank· DDBJ | AAK83055.1 EMBL· GenBank· DDBJ | mRNA | ||
AABR06060567 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
AABR06060568 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
CH473965 EMBL· GenBank· DDBJ | EDL98978.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH473965 EMBL· GenBank· DDBJ | EDL98979.1 EMBL· GenBank· DDBJ | Genomic DNA |