Q9JHX4 · CASP8_RAT

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).

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).
    EC:3.4.22.61 (UniProtKB | ENZYME | Rhea)

Activity regulation

CASP8 activity is restricted by RIPK1.

Features

Showing features for site, active site.

TypeIDPosition(s)Description
Site218-219Cleavage; by autocatalytic cleavage
Active site319
Active site362
Site376-377Cleavage; by CASP6
Site388-389Cleavage; by autocatalytic cleavage

GO annotations

AspectTerm
Cellular ComponentCD95 death-inducing signaling complex
Cellular Componentcell body
Cellular Componentcytoplasm
Cellular Componentcytosol
Cellular Componentdeath-inducing signaling complex
Cellular Componentlamellipodium
Cellular ComponentNoc1p-Noc2p complex
Cellular Componentnucleoplasm
Cellular Componentnucleus
Cellular Componentplasma membrane
Cellular Componentprotein-containing complex
Cellular Componentripoptosome
Molecular Functioncysteine-type endopeptidase activator activity involved in apoptotic process
Molecular Functioncysteine-type endopeptidase activity
Molecular Functioncysteine-type endopeptidase activity involved in apoptotic process
Molecular Functioncysteine-type endopeptidase activity involved in apoptotic signaling pathway
Molecular Functiondeath effector domain binding
Molecular Functiondeath receptor binding
Molecular Functionendopeptidase activity
Molecular Functionidentical protein binding
Molecular Functionpeptidase activity
Molecular Functionprotein-containing complex binding
Molecular Functionscaffold protein binding
Molecular Functiontumor necrosis factor receptor binding
Molecular Functionubiquitin protein ligase binding
Biological Processactivation of cysteine-type endopeptidase activity
Biological Processangiogenesis
Biological Processapoptotic process
Biological Processapoptotic signaling pathway
Biological Processcellular response to mechanical stimulus
Biological Processcellular response to organic cyclic compound
Biological Processexecution phase of apoptosis
Biological Processextrinsic apoptotic signaling pathway
Biological Processextrinsic apoptotic signaling pathway via death domain receptors
Biological Processheart development
Biological Processhepatocyte apoptotic process
Biological Processmacrophage differentiation
Biological Processnecroptotic process
Biological Processnegative regulation of canonical NF-kappaB signal transduction
Biological Processnegative regulation of necroptotic process
Biological Processneural tube formation
Biological Processpositive regulation of apoptotic process
Biological Processpositive regulation of canonical NF-kappaB signal transduction
Biological Processpositive regulation of cell migration
Biological Processpositive regulation of execution phase of apoptosis
Biological Processpositive regulation of extrinsic apoptotic signaling pathway
Biological Processpositive regulation of interleukin-1 beta production
Biological Processpositive regulation of macrophage differentiation
Biological Processpositive regulation of neuron apoptotic process
Biological Processpositive regulation of proteolysis
Biological Processprotein maturation
Biological Processprotein processing
Biological Processproteolysis
Biological Processproteolysis involved in protein catabolic process
Biological Processpyroptotic inflammatory response
Biological Processregulation of apoptotic signaling pathway
Biological Processregulation of cytokine production
Biological Processregulation of innate immune response
Biological Processregulation of thymocyte apoptotic process
Biological Processresponse to cobalt ion
Biological Processresponse to estradiol
Biological Processresponse to ethanol
Biological Processresponse to lipopolysaccharide
Biological Processresponse to tumor necrosis factor
Biological Processself proteolysis
Biological ProcessTRAIL-activated apoptotic signaling pathway

Keywords

Enzyme and pathway databases

Protein family/group databases

Names & Taxonomy

Protein names

Gene names

    • Name
      Casp8

Organism names

  • Taxonomic identifier
  • Strains
    • Sprague-Dawley
    • Brown Norway
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Rattus

Accessions

  • Primary accession
    Q9JHX4

Proteomes

Organism-specific databases

PTM/Processing

Features

Showing features for propeptide, modified residue, chain.

TypeIDPosition(s)Description
PropeptidePRO_00004324251-218
Modified residue188Phosphoserine
Modified residue213Phosphoserine
ChainPRO_0000432426219-378Caspase-8 subunit p18
Modified residue336Phosphotyrosine
PropeptidePRO_0000432427379-388
ChainPRO_0000432428389-482Caspase-8 subunit p10
Modified residue390Phosphoserine; by CDK1

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

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).

Binary interactions

TypeEntry 1Entry 2Number of experimentsIntact
BINARY Q9JHX4Fadd Q8R2E72EBI-4326675, EBI-4326723

Protein-protein interaction databases

Structure

Family & Domains

Features

Showing features for domain.

TypeIDPosition(s)Description
Domain2-80DED 1
Domain100-177DED 2

Sequence similarities

Belongs to the peptidase C14A family.

Keywords

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Sequence processing
    The displayed sequence is further processed into a mature form.
  • Length
    482
  • Mass (Da)
    55,339
  • Last updated
    2000-10-01 v1
  • Checksum
    82B4A29330C53264
MDFHSCLYDIAERLGNEELAALKFLCLDHIPQKKQESINDVLVLFQRLQEEGMLEEDNLSFLKELLFHISRRDLLSRVLKSSPEEMVRELQVLGKAQVSAYRVMLFKLSEDMDKEDLKSFKFLLITEIPKCKLQDNSSLLDIFVEMEKRTILAENNLVTLKSICFRVNRSLLGRIDDYERSSTERRMSTEGGEELPVSVLDEVTIKMQDMWDSPGEQESESLNSDNVYQMKSKPRGYCLIFNNNNFSKAREDIPKLSNMRDRKGTNYDEEALSKTFKELHFEIVSFSDCTASQIHEVLVSYQSKDHKGKDCFICCILSHGDKGIVYGTDGKEASIYELTSYFTGSKCPSLAGKPKIFFIQACQGNNFQKAVPVPDETGLEQEHVLEEDSSSYKNYIPDEADFLLGMATVKNCVSYRDPTRGTWYIQSLCQSLRERCPRGEDILSILTGVNYDVSNKDNPRNMGKQMPQPIFTLRKKLFFPPN

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
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

Genome annotation databases

Similar Proteins

Disclaimer

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