Caspase-8 - Q9JHX4 (CASP8_RAT)


Protein Feature View of PDB entries mapped to a UniProtKB sequence  

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 the TNFRSF6/FAS 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 TNFRSF6/FAS mediated or TNFRSF1A (PubMed:10197541). The resulting aggregate called 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-D (GSDMD): GSDMD cleavage promoting release of the N-terminal moiety (Gasdermin-D, N-terminal) that binds to membranes and forms pores, triggering pyroptosis (By similarity). Initiates pyroptosis following inactivation of MAP3K7/TAK1 (By similarity). May participate in the Granzyme B (GZMB) cell death pathways (By similarity). Cleaves PARP1 (By similarity). UniProt
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. UniProt
Pathway Maps
      ESCHER  BiGG
Subunit Structure
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). Interacts with FADD, 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). UniProt
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