3.4.22.61: caspase-8
This is an abbreviated version!
For detailed information about caspase-8, go to the full flat file.
Word Map on EC 3.4.22.61
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3.4.22.61
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caspase-9
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bcl-2
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necrosis
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extrinsic
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bid
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tnf
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trail
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apoptosis-inducing
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parp
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pro-apoptotic
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anti-apoptotic
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leukemia
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fas-associated
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trail-induced
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tunel
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fasl
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annexin
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death-inducing
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factor-related
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caspase-dependent
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c-flips
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apoptosis-related
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xiap
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fas-mediated
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flip
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receptor-mediated
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nf-kappab
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polyadp-ribose
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jurkat
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necroptosis
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anti-fas
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deoxynucleotidyl
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adp-ribose
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pan-caspase
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z-vad-fmk
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tnf-related
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deltapsim
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mitochondria-dependent
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fas-induced
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survivin
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receptor-induced
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tnf-induced
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receptor-interacting
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mlkl
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mitochondria-mediated
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ripk1
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sub-g1
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apaf-1
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executioner
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drug development
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procaspase-3
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medicine
- 3.4.22.61
- caspase-9
- bcl-2
- necrosis
-
extrinsic
- bid
- tnf
-
trail
-
apoptosis-inducing
- parp
-
pro-apoptotic
-
anti-apoptotic
- leukemia
-
fas-associated
-
trail-induced
-
tunel
- fasl
-
annexin
-
death-inducing
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factor-related
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caspase-dependent
- c-flips
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apoptosis-related
- xiap
-
fas-mediated
- flip
-
receptor-mediated
- nf-kappab
-
polyadp-ribose
-
jurkat
-
necroptosis
-
anti-fas
-
deoxynucleotidyl
- adp-ribose
-
pan-caspase
- z-vad-fmk
-
tnf-related
-
deltapsim
-
mitochondria-dependent
-
fas-induced
- survivin
-
receptor-induced
-
tnf-induced
-
receptor-interacting
- mlkl
-
mitochondria-mediated
- ripk1
-
sub-g1
- apaf-1
-
executioner
- drug development
- procaspase-3
- medicine
Reaction
strict requirement for Asp at position P1 and has a preferred cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-/-(Gly/Ser/Ala) =
Synonyms
apoptotic cysteine protease, apoptotic protease Mch-5, C14.004, CAP4, Casp8, caspase 8, caspase-8, cysteine aspartic acid protease 8, cysteine aspartic acid-specific protease, cysteine protease caspase-8, FADD-homologous ICE/CED-3-like protease, FADD-like ICE, FLICE, FLICE/MACH, ICE-like apoptotic protease 5, MACH, Mch5, More, MORT1-associated CED-3 homolog
ECTree
3.4.22.61 caspase-8Advanced search results
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results (General Information
General Information on EC 3.4.22.61 - caspase-8
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GENERAL INFORMATION 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
evolution
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initiator and executioner caspases, the pro-apoptotic members of the caspase family are subdivided in the initiators of apoptosis and the executioners of apoptosis. Caspase-18 and the ancestor of -8 and -10 called caspase-810 in this schematic are still found in fishes. Later on in evolution, caspase-8 and -10 branched off from caspase-810
evolution
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initiator and executioner caspases, the pro-apoptotic members of the caspase family are subdivided in the initiators of apoptosis, i.e. caspases-8, -9 and -10 in humans, and the executioners of apoptosis, caspase-3, -6 and -7, phylogenetic tree of all the human caspases, overview. The initiators have a relatively large N-terminal dimerization domain, either a death effector domain, caspases-8 and -10, or a structurally related caspase recruitment domain, caspase-9. Caspase-18 and the ancestor of -8 and -10 called caspase-810 in this schematic are still found in fishes. Later on in evolution, caspase-8 and -10 branched off from caspase-810
malfunction
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depletion of caspase-8 decreases endogenous amyloid beta-protein production
malfunction
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silencing of caspase 8 gene is a key factor controlling the outcome of neonatal astrocytes upon Fas engagement, restoration of caspase 8 expression triggers apoptotic cell death in primary neonatal astrocytes
malfunction
caspase 8 knockdown stabilizes both cellular inhibitor of apoptosis 1, cIAP-1, and X-linked IAP, XIAP
malfunction
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cells lacking in caspase-8 show reduced adhesion to fibronectin with concomitant reduction in adhesion-induced ERK 1/2 activation, these effects can be restored upon reexpression of either the wild-type or catalytically inactive point mutant protein, implying caspase-8 is involved to promote cell adhesion and adhesion-induced ERK 1/2 activation independently of its catalytical activity
malfunction
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in p62-deficient cancer cells caspase-8 activity and apoptosis are diminished, yet not abrogated
malfunction
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loss of caspase 8 prevents CYLD degradation, resulting in necrotic death. Mutation of the caspase 8 processing site on the substrate converts a pro-survival response to necrotic death without the need for caspase 8 inhibition
malfunction
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loss of caspase 8 prevents CYLD degradation, resulting in necrotic death. Mutation of the caspase 8 processing site on the substrate converts a pro-survival response to necrotic death without the need for caspase 8 inhibition
malfunction
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mice deficient in caspase-8 in basal epidermal keratinocytes suffer from chronic skin inflammation, as an apparent consequence of IRF3 hyper-activation. Catalytically active caspase-8 is required to rescue the lymphocyte development in caspase-8 deficient mice. The developmental phenotype observed in the caspase-8 knockout mouse is shared with both the FLIPL knockout and the FADD knockout
malfunction
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no change in A-SMase activity in caspase-8-deficient cells. Retransfection of caspase-8-deficient Jurkat cells with an expression plasmid for caspase-8 restores the ability of the transfected cells to respond to TNF stimulation by increased A-SMase activity. Caspase-8-deficient Jurkat cells are almost completely resistant to TNF/CHX treatment
malfunction
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proliferative defects of caspase 8-deficient T cells and B cells. Caspase-8 deficiency causes programmed necrotic cell death
malfunction
caspase-8 is coupled with the regulation of various neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease and dentatorubral pallidoluysian atrophy
malfunction
failure to express caspase-8 has no effect on the life-span of dendritic cells but instead leads to an enhanced intrinsic activation and subsequently more mature and autoreactive lymphocytes. Mice with conditional deletion of caspase-8 in DCs develop a chronic systemic autoimmune disease
metabolism
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caspase-8 of the extrinsic pathway is able to activate upstream mediators of the intrinsic apoptotic pathway
metabolism
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caspase-8 and Bid are the known procurers of the death signal leading from death receptor stimulation to permeabilisation of the outer mitochondrial membrane in the apoptotic pathway, regulation of caspase-8 and Bid function and activation, overview
metabolism
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mathematical modeling of CD95 DISC-mediated MAPK activation and apoptosis, overview. Quantitative dynamics of DED proteins, procaspase-8, and c-FLIP, which lead to caspase-8 activation and induction of apoptotic and non-apoptotic signaling pathways
metabolism
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recruitment of caspase 8 and FLIP to a RIPK1-containing complex determines cell fate, overview
metabolism
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the interaction of phosphorylated caspase-8 with regulatory subunit, p85alpha, of phosphatidylinositol-3-OH kinase enhances Rac activation to promote cell migration, requiring Tyr380 and phosphorylation by c-src
metabolism
model of caspase 8 activation. Upon apoptosis induction triggered by interaction of the death ligand to the trimeric death receptor, adaptor FADD (Fas-associated protein with death domain ) is recruited to the death receptor via a death domain DD-DD interaction. FADD recruited at cell surface can recruit caspase-8 via a DED-DED interaction, leading to procaspase-8 proximity to meet another procaspase-8. Closely located FL motif on DED2 causes domain swapping and dimerization of procaspase-8. The dimerization via tandem DED domain swapping causes the proximity-mediated self-activation of caspase-8
physiological function
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activation of caspase 8 is involved in Fas-induced apoptosis in neonatal astrocytes
physiological function
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apoptosis is mediated with caspase-8 activation
physiological function
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caspase 8 is a key molecule of apoptosis in hepatocellular carcinoma. Methylation of caspase 8 and positive expression of its gene product is significantly correlated with high apoptotic indices
physiological function
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caspase 8 is involved in apoptosis, trophoblast differentiation process, regulation of inflammatory processes, lymphocyte proliferation, cell migration, and cell differentiation with or without enucleation
physiological function
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caspase-8 is involved in the presenilin1/gamma-secretase-dependent cleavage of amyloid precursor protein after the induction of apoptosis
physiological function
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caspase-8 is not essential in goniothalamin-induced apoptosis
physiological function
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caspase-8-dependent apoptosis is demonstrated by cleavage of caspase-8 after recombinant eosinophil cationic protein treatment
physiological function
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neuronal death in Tg(DELTACR) mice is not accompanied by activation of caspase-8
physiological function
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NPI-0052 plus lenalidomide-triggered apoptosis is primarily dependent on caspase-8 signaling
physiological function
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programmed cell death involves the caspase-8-dependent extrinsic pathway
physiological function
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the Fas-associated protein with a death domain and subsequent activated caspase-8 are responsible for double-stranded RNA-dependent protein kinase-induced apoptosis in recombinant virus-infected cells
physiological function
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caspase 8 can initiate apoptosis in response to cell surface receptor activation, but it is also required for embryonic development and immune cell proliferation, defined by suppression of receptor-interacting protein kinase 3, a kinase that triggers an alternative form of cell death called programmed necrosis. The extrinsic apoptosis, is mediated by a group of receptors of the tumour necrosis factor, TNF, superfamily called the death receptors. Caspase 8 is further implicated in cell motility, metastasis, and suppression of inflammation. The non-apoptotic roles of FADD and caspase 8 are involved the suppression of RIPK3-dependent programmed necrosis, the caspase 8FLIP heterodimer is implicated in carrying out the suppression of RIPK3 signalling. Mechanism of caspase 8 activation, detailed overview
physiological function
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caspase 8 inhibits programmed necrosis by processing CYLD. Suppression of necrotic cell death by caspase 8 requires its catalytic activity but not the autocleavage essential for apoptosis. CYLD is cleaved by caspase 8 to promote survival
physiological function
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caspase 8 inhibits programmed necrosis by processing CYLD. Suppression of necrotic cell death by caspase 8 requires its catalytic activity but not the autocleavage essential for apoptosis. CYLD is cleaved by caspase 8 to promote survival. TNF-treated caspase-8-sufficient Jurkat T cells dying by apoptosis but remain unchanged in the caspase-8-deficient cells dying by necrosis
physiological function
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caspase 8 is an initiator caspase for caspase 3 during H2O2-induced apoptosis
physiological function
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caspase-8 activity has an essential role in CD95/Fas-mediated MAPK activation. Stimulation of CD95/Fas/APO-1 results in the induction of both apoptotic and non-apoptotic signaling pathways. CD95 DISC-induced caspase-8 activity is important for the initiation of ERK1/2 and p38 MAPK activation, caspase-8 activation mechanism, overview. The long c-FLIP isoform, c-FLIPL, and the short c-FLIP isoform, c-FLIPR, inhibit MAPK induction by blocking caspase-8 processing at the DISC. Caspase-8 activity is also essential to MAPK activation in response to anti-APO-1 stimulation
physiological function
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caspase-8 and caspase-7 sequentially mediate proteolytic activation of acid sphingomyelinase in TNF-R1 receptosomes. TNF-induced A-SMase activation strictly depends on functional caspase-8 and caspase-7 expression
physiological function
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caspase-8 cleavage of the interleukin-21, IL-21, receptor is a negative feedback regulation of IL-21 signaling. Caspase-3 and the BH3 interacting domain death agonist, Bid, are cleaved by CASP8 as part of the apoptotic pathway
physiological function
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caspase-8, the initiator of extrinsically-triggered apoptosis, also has important functions in cellular activation and differentiation downstream of a variety of cell surface receptors. The heterodimer of caspase-8 with the long isoform of cellular FLIP, FLIPL, fulfills these pro-survival functions of caspase-8. Caspase-8 has important functions in survival and development, caspase-8 activation not only triggers apoptosis but is also essential for embryonic development. Tissue specific knockout of caspase-8 revealed an essential role for this caspase in the development of a variety of tissues,most notably the endothelial cells of the heart and vascular system, lymphocytes and monocytes. Caspase-8 in programmed necrosis, detailed overview
physiological function
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caspase-8, the initiator of extrinsically-triggered apoptosis, also has important functions in cellular activation and differentiation downstream of a variety of cell surface receptors. The heterodimer of caspase-8 with the long isoform of cellular FLIP, FLIPL, fulfills these pro-survival functions of caspase-8. Caspase-8 has important functions in survival and development. Caspase-8 in programmed necrosis, detailed overview
physiological function
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DISC-activated caspase-8 and -10 trigger a caspase cascade by cleavage of caspase-3. Caspase-8 and Bid are the known procurers of the death signal leading from death receptor stimulation to permeabilisation of the outer mitochondrial membrane in the apoptotic pathway, regulation of caspase-8 and Bid function and activation, overview. In type II cells activation of the mitochondrial arm of the apoptosis pathway is required for the induction of apoptosis following a death receptor stimulus. The bridging element between the two arms of the apoptosis pathway is the caspase-8-mediated cleavage of the pro-apoptotic Bcl-2 family member Bid. The anionic mitochondria-specific phospho-lipid cardiolipin acts as a mitochondria-associated platform that is actually required for caspase-8 translocation, oligomerisation and activation after CD95 stimulation, and hence CD95-induced death in type II cells. In type I cells caspase-8 activation at the DISC is very efficient, resulting in direct activation of caspase-3 and the caspase cascade
physiological function
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FADD-dependent formation of heterodimers between caspase-8 and FLIPL mediates the developmental role of caspase-8. The catalytic domain of caspase-8 is crucial for its activity in the context of activation by homodimerization. Mechanism of caspase-8 functional divergence in apoptotic and non-apoptotic pathways, overview
physiological function
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mature caspase-8 cleaves a huge number of different cellular substrates in the cytosol. Under apoptotic stimuli, caspase-8 undergoes catalytic autocleavage to generate the proapoptotic mature tetramer to induce apoptosis
physiological function
Tumor necrosis factorrelated apoptosis-inducing ligand, TRAIL, induces degradation of cellular inhibitor of apoptosis 1, cIAP-1, requiring caspase 8 activity, for, at least in part, direct cleavage of cIAP-1 by caspase 8. Cellular depletion of cIAP-1 enhances the efficiency of TRAIL-mediated apoptosis. cIAP-1 and cIAP-2 are responsible for Lys-63 polyubiquitination of RIP1 in cancer cells, which, in turn, results in activation of NF-kappaBmediated survival signals
physiological function
caspase-8 acts as a molecular rheostat to limit RIPK1- and MyD88-mediated dendritic cell activation
physiological function
cleavage of Atg3 protein by caspase-8 regulates autophagy during receptor-activated cell death
physiological function
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targeting of caspase-8 substrates to the plasma membrane accelerates apoptosis
physiological function
the enzyme is a key mediator of neuronal apoptosis
physiological function
caspase-10 negatively regulates caspase-8-mediated cell death. Caspase-10 reduces death-inducing signaling complex DISC association and activation of caspase-8. Caspase-10 does not compete with caspase-8 for binding to adaptor protein FADD. Caspase-8 is required upstream of both regulator cFLIP and caspase-10 and DISC formation critically depends on the scaffold function of caspase-8. Caspase-10 rewires DISC signaling to NF-kappaB activation/cell survival and the catalytic activity of caspase-10, and caspase-8, is redundant in gene induction
physiological function
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caspase-8 of fish may play an essential role in ammonia induced apoptosis. Caspase-8 transcripts are detected in liver after exposure to ammonia. Caspase-8 cleaved fragment is detected and significant alteration of procaspase-8 level is found with the same ammonia treatment condition. Remarkable changes of immunopositive staining are observed after ammonia treatment
physiological function
cleavage by caspase 8 and the subsequent association with the outer mitochondrial membrane are two critical events that activate BH3-only protein Bid during death receptor-mediated apoptosis
physiological function
infection by Trypanosoma cruzi induces caspase-8 activity and caspase-8 inhibition increases trophoblast cells infection while decreases parasite-induced cellular differentiation and apoptotic cell death, but not cellular proliferation
physiological function
interleukin-1beta production after hypoxia might be associated with caspase-8 rather than caspase-1
additional information
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active caspase-8 colocalizes with internalized TNF-R1 receptosomes
additional information
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FLIPL, a catalytically defective caspase-8 paralog, can interact with caspase-8 to activate its catalytic function. The caspase-8/FLIPL heterodimer has a restricted substrate repertoire and does not induce apoptosis. Caspase-8 heterodimerized with FLIPL prevents the receptor interacting kinases RIPK1 and -3 from executing the form of cell death known as necroptosis
additional information
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FLIPL, a catalytically defective caspase-8 paralog, can interact with caspase-8 to activate its catalytic function. The caspase-8/FLIPL heterodimer has a restricted substrate repertoire and does not induce apoptosis. Caspase-8 heterodimerized with FLIPL prevents the receptor interacting kinases RIPK1 and -3 from executing the form of cell death known as necroptosis
additional information
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following caspase-8 recruitment to the DISC, the E3 ligase cullin-3 is able to ubiquitinate caspase-8 which in turn recruits the ubiquitin-binding protein p62, caspase-8 polyubiquitination by cullin-3 and its subsequent p62-dependent aggregation stabilises active caspase-8 and thereby positively regulates apoptosis. The caspase-8/cullin-3/p62 complex is translocates to the cytosol from where it induces apoptosis in a p62-dependent manner
