Caspase activation via death receptors in the presence of ligand (Homo sapiens)

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10, 19, 26, 37, 3810, 117, 8, 15, 21, 26...2, 25, 351, 3, 4, 8, 12...14, 16, 17, 29, 378, 26, 379, 14, 3712, 24, 32, 3622, 27, 28, 32cytosolendosomeFADD CASP8(1-479) RIPK1 CFLAR(1-376) TRADD CASP8(1-374) FADD MyrG-p-S16-TICAM2 TRADD FADD CASP8(1-479) CFLAR(1-480) FASLG(1-281) GPIN-CD14(20-345) FADD LPS GPIN-CD14(20-345) LY96 LPS FAS DISC:procaspase-8:FLIP(L)RIPK1 TNFRSF10B TNFSF10 FASL:FASReceptorTrimer:FADD:pro-Caspase-8:FLIP(L)FADD Death ReceptorSignallingCASP8(1-479) CASP8(1-479) CASP8(1-479) TNFRSF10A TRADD FADD TRAF2 TNFSF10 FADD CASP8(1-479) FAS CFLAR(1-480) TLR4 DISCCASP8(1-479) TICAM1 RIPK1 FADD TNFSF10:TNFRSF10A,B:FADD:2xCASP8(1-479)FADD TRADD:TRAF2:RIP1:FADD:procaspase-8:FLIP(L)TNFSF10 CFLAR(1-480)TRADD:TRAF2:RIP1:FADD:CASP8(1-479)TRADD FASLG(1-281) TNFRSF10A TRAF2 activatedTLR3/TLR4:TRIF:RIP1:FADD:pro-caspase-8CASP8(1-479) MyD88-independentTLR3/TLR4 cascade DISC:p43/p41CASP8:p43 FLIP(L)RIPK1(325-671) CASP8(1-479) FADD TICAM1 TNFRSF10B TLR3 TLR3 FASLG(1-281) CASP8(217-374) FASL:FASreceptortrimer:FADD:procaspase-8-dimerCFLAR(377-480)RIPK1 TNFSF10 RIPK1 FADD TRAF2 FAS TLR4 TNFRSF10A TNFRSF10B TNFSF10:TNFRSF10A,B:FADD:CASP8(1-479)TICAM1 CASP8(1-479) TRAF2:TRADD:RIP1:FADD:2xCASP8(1-479)active caspase-8CASP8(385-479) TNFRSF10A CFLAR(1-480) CASP8(1-479) TNFRSF10B TNFRSF10B FASLG(1-281) FAS activatedTLR3/TLR4:TRIF:RIP1:FADDFASLG(1-281) MyrG-p-S16-TICAM2 TICAM1 TRADD FAS TNFSF10:TNFRSF10A,B:FADD:CASP8(1-479):CFLARDISC:procaspase-8-dimerCFLAR(1-480) TNFSF10 FADD RIPK1 FADD CASP8(1-479)TNFRSF10A viral c-FLIPhomologueFLIP(S)TRAF2 TRAF2 FASL:FAStrimer:FADD:CASP8(1-479)LY96 5553121, 337, 21, 30, 3355556, 18459551355511, 2313, 20


Description

Caspase-8 is synthesized as zymogen (procaspase-8) and is formed from procaspase-8 as a cleavage product. However, the cleavage itself appears not to be sufficient for the formation of an active caspase-8. Only the coordinated dimerization and cleavage of the zymogen produce efficient activation in vitro and apoptosis in cellular systems [Boatright KM and Salvesen GS 2003; Keller N et al 2010; Oberst A et al 2010].

The caspase-8 zymogens are present in the cells as inactive monomers, which are recruited to the death-inducing signaling complex (DISC) by homophilic interactions with the DED domain of FADD. The monomeric zymogens undergo dimerization and the subsequent conformational changes at the receptor complex, which results in the formation of catalytically active form of procaspase-8.[Boatright KM et al 2003; Donepudi M et al 2003; Keller N et al 2010; Oberst A et al 2010]. Source:Reactome.</div>

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Bibliography

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History

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CompareRevisionActionTimeUserComment
117671view11:59, 22 May 2021EweitzModified title
114773view16:26, 25 January 2021ReactomeTeamReactome version 75
113217view11:28, 2 November 2020ReactomeTeamReactome version 74
112441view15:38, 9 October 2020ReactomeTeamReactome version 73
101346view11:23, 1 November 2018ReactomeTeamreactome version 66
100884view20:57, 31 October 2018ReactomeTeamreactome version 65
100425view19:31, 31 October 2018ReactomeTeamreactome version 64
99974view16:15, 31 October 2018ReactomeTeamreactome version 63
99529view14:51, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93835view13:39, 16 August 2017ReactomeTeamreactome version 61
93390view11:22, 9 August 2017ReactomeTeamreactome version 61
87868view12:09, 25 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86476view09:19, 11 July 2016ReactomeTeamreactome version 56
83347view10:55, 18 November 2015ReactomeTeamVersion54
81505view13:02, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
CASP8(1-374) ProteinQ14790 (Uniprot-TrEMBL)
CASP8(1-479) ProteinQ14790 (Uniprot-TrEMBL)
CASP8(1-479)ProteinQ14790 (Uniprot-TrEMBL)
CASP8(217-374) ProteinQ14790 (Uniprot-TrEMBL)
CASP8(385-479) ProteinQ14790 (Uniprot-TrEMBL)
CFLAR(1-376) ProteinO15519-1 (Uniprot-TrEMBL)
CFLAR(1-480) ProteinO15519-1 (Uniprot-TrEMBL)
CFLAR(1-480)ProteinO15519-1 (Uniprot-TrEMBL)
CFLAR(377-480)ProteinO15519-1 (Uniprot-TrEMBL)
DISC:p43/p41CASP8:p43 FLIP(L)ComplexR-HSA-3465431 (Reactome)
DISC:procaspase-8-dimerR-HSA-2671813 (Reactome)
DISC:procaspase-8:FLIP(L)ComplexR-HSA-3371381 (Reactome)
DISCR-HSA-2671814 (Reactome)
Death Receptor SignallingPathwayR-HSA-73887 (Reactome) The death receptors, all cell-surface receptors, begin the process of caspase activation. The common feature of these type 1 transmembrane proteins is the "death-domain" a conserved cytoplasmic motif found on all of the three receptors (FAS/CD95, TNF-receptor, and TRAIL-receptor) that binds the Fas-associated protein with death domain (FADD). Ligand binding to death receptors (DR) results in receptor oligomerization and recruitment of adaptor proteins via homophilic interaction of death domains. This project describes an assembly of the death-inducing signaling complex (DISC) and shows protein composition and stoichiometry within the DISC. It also provides the appropriate literature references if available. However, the DISC signaling complex may vary in its components stoichiometry. DR signaling may trigger formation of higher order receptor structures or signaling through rearrangement of receptor chains, which is not reflected here.
FADD ProteinQ13158 (Uniprot-TrEMBL)
FAS ProteinP25445 (Uniprot-TrEMBL)
FASL:FAS

Receptor

Trimer:FADD:pro-Caspase-8:FLIP(L)		ComplexR-HSA-3465499 (Reactome)
FASL:FAS

receptor

trimer:FADD:procaspase-8-dimer		ComplexR-HSA-2671811 (Reactome)
FASL:FAS trimer:FADD:CASP8(1-479)ComplexR-HSA-75114 (Reactome)
FASLG(1-281) ProteinP48023 (Uniprot-TrEMBL)
FLIP(S)ProteinO15519-2 (Uniprot-TrEMBL)
GPIN-CD14(20-345) ProteinP08571 (Uniprot-TrEMBL)
LPS MetaboliteCHEBI:16412 (ChEBI)
LY96 ProteinQ9Y6Y9 (Uniprot-TrEMBL)
MyD88-independent TLR3/TLR4 cascade PathwayR-HSA-166166 (Reactome) MyD88-independent signaling pathway is shared by TLR3 and TLR4 cascades. TIR-domain-containing adapter-inducing interferon-beta (TRIF or TICAM1) is a key adapter molecule in transducing signals from TLR3 and TLR4 in a MyD88-independent manner (Yamamoto M et al. 2003a). TRIF is recruited to ligand-stimulated TLR3 or 4 complex via its TIR domain. TLR3 directly binds TRIF (Oshiumi H et al 2003). In contrast, TLR4-mediated signaling pathway requires two adapter molecules, TRAM (TRIF-related adapter molecule or TICAM2) and TRIF. TRAM(TICAM2) is thought to bridge between the activated TLR4 complex and TRIF (Yamamoto M et al. 2003b, Tanimura N et al. 2008, Kagan LC et al. 2008).

TRIF recruitment to TLR complex stimulates distinct pathways leading to production of type 1 interferons (IFNs), pro-inflammatory cytokines and induction of programmed cell death.

MyrG-p-S16-TICAM2 ProteinQ86XR7 (Uniprot-TrEMBL)
RIPK1 ProteinQ13546 (Uniprot-TrEMBL)
RIPK1(325-671) ProteinQ13546 (Uniprot-TrEMBL)
TICAM1 ProteinQ8IUC6 (Uniprot-TrEMBL)
TLR3 ProteinO15455 (Uniprot-TrEMBL)
TLR4 ProteinO00206 (Uniprot-TrEMBL)
TNFRSF10A ProteinO00220 (Uniprot-TrEMBL)
TNFRSF10B ProteinO14763 (Uniprot-TrEMBL)
TNFSF10 ProteinP50591 (Uniprot-TrEMBL)
TNFSF10:TNFRSF10A,B:FADD:2xCASP8(1-479)ComplexR-HSA-2671816 (Reactome)
TNFSF10:TNFRSF10A,B:FADD:CASP8(1-479):CFLARComplexR-HSA-3371390 (Reactome)
TNFSF10:TNFRSF10A,B:FADD:CASP8(1-479)ComplexR-HSA-5637468 (Reactome)
TRADD ProteinQ15628 (Uniprot-TrEMBL)
TRADD:TRAF2:RIP1:FADD:CASP8(1-479)ComplexR-HSA-140976 (Reactome)
TRADD:TRAF2:RIP1:FADD:procaspase-8:FLIP(L)ComplexR-HSA-3465532 (Reactome)
TRAF2 ProteinQ12933 (Uniprot-TrEMBL)
TRAF2:TRADD:RIP1:FADD:2xCASP8(1-479)ComplexR-HSA-2671812 (Reactome)
activated TLR3/TLR4:TRIF:RIP1:FADD:pro-caspase-8ComplexR-HSA-2562542 (Reactome)
activated TLR3/TLR4:TRIF:RIP1:FADDComplexR-HSA-2562577 (Reactome)
active caspase-8ComplexR-HSA-2562550 (Reactome)
viral c-FLIP homologueR-MCV-2671796 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
CASP8(1-479)R-HSA-141156 (Reactome)
CASP8(1-479)R-HSA-141159 (Reactome)
CASP8(1-479)R-HSA-73945 (Reactome)
CFLAR(1-480)R-HSA-3371359 (Reactome)
CFLAR(1-480)R-HSA-3371360 (Reactome)
CFLAR(1-480)R-HSA-3465459 (Reactome)
CFLAR(377-480)ArrowR-HSA-3465448 (Reactome)
DISC:p43/p41CASP8:p43 FLIP(L)ArrowR-HSA-3465448 (Reactome)
DISC:procaspase-8-dimerR-HSA-139952 (Reactome)
DISC:procaspase-8:FLIP(L)R-HSA-3465448 (Reactome)
DISCArrowR-HSA-139952 (Reactome)
FASL:FAS

Receptor

Trimer:FADD:pro-Caspase-8:FLIP(L)		ArrowR-HSA-3465459 (Reactome)
FASL:FAS

receptor

trimer:FADD:procaspase-8-dimer		ArrowR-HSA-73945 (Reactome)
FASL:FAS trimer:FADD:CASP8(1-479)R-HSA-3465459 (Reactome)
FASL:FAS trimer:FADD:CASP8(1-479)R-HSA-73945 (Reactome)
FLIP(S)TBarR-HSA-141156 (Reactome)
FLIP(S)TBarR-HSA-141159 (Reactome)
FLIP(S)TBarR-HSA-73945 (Reactome)
R-HSA-139952 (Reactome) Caspase-8 zymogens are present in the cells as inactive monomers, containing a large N-terminal prodomain with two death effector domains (DED), and a C-terminal catalytic subunit composed of small and a large domains separated by a smaller linker region [Donepudi M et al 2003; Keller N et al 2009]. Dimerization is required for the caspase-8 activation [Donepudi M et al 2003]. Once dimerized, caspase-8 zymogen undergoes a series of autoproteolytic cleavage events at aspartic acid residues in their interdomain linker regions. A second cleavage event between the the N-terminal prodomain and the catalytic domain releases the active caspase from the activation complex into the cytosol. The resulting fully active enzyme is a homodimer of catalytic domains, where each domain is composed of a large p18 and a small p10 subunit [Keller N et al 2009; Oberst A et al 2010].
R-HSA-141156 (Reactome) Monomeric caspase-8 zymogens undergo dimerization and subsequent conformational changes at the TRAIL:TRAIL receptor-2:FADD receptor complex leading to the formation of the catalytically active form of procaspase-8.
R-HSA-141159 (Reactome) Monomeric caspase-8 zymogens undergo dimerization and subsequent conformational changes at the TRADD:TRAF2:RIP1:FADD:Capase-8 receptor complex leading to the formation of the catalytically active form of procaspase-8.
R-HSA-2562564 (Reactome) TLR3/4 signaling component were shown to mediate apoptosis in various human cell lines in the FADD:caspasse-8-dependent manner [Kalai M et al 2002; Kaiser WJ and Offermann MK 2005; Estornes Y et al 2012]. Caspase-8 zymogens (procaspase-8) are present in the cells as inactive monomers, containing a large N-terminal prodomain with two death effector domains (DED), and a C-terminal catalytic subunit composed of small and a large domains separated by a smaller linker region [Donepudi M et al 2003; Keller N et al 2009]. Dimerization is required for caspase-8 activation [Donepudi M et al 2003]. The dimerization event occurs at the receptor signaling complex. Once dimerized, caspase-8 zymogen undergoes a series of autoproteolytic cleavage events at aspartic acid residues in their interdomain linker regions. A second cleavage event between the the N-terminal prodomain and the catalytic domain releases the active caspase from the activation complex into the cytosol. The resulting fully active enzyme is a homodimer of catalytic domains, where each domain is compsed of a large p18 and a small p10 subunit [Keller N et al 2009; Oberst A et al 2010].
R-HSA-3371359 (Reactome) Pro-caspase-8 and FLIP(L) are recruited to the DISC. Following recruitment to the DISC, FLIP-L forms a heterodimer with caspase-8 through both death effector domain (DED) and caspase-like domain (CLD). In addition, FLIP(L) can also regulate signaling via interaction with the DED of FADD. The regulatory function of FLIP(L) has been found to differ depending on its expression levels. FLIP(L) was shown to inhibit death receptor (DR)-mediated apoptosis only when expressed at high levels, while low cell levels of FLIP(L) enhanced DR signaling to apoptosis (Sharp DA et al. 2005; Siegmund D et al. 2002; Boatright KM et al. 2004; Okano H et al. 2003; Yerbes R et al. 2011). The expression levels of c-FLIP proteins were shown to be regulated by NFkappaB signaling pathway (Micheau O et a. 2001; Kreuz S et al 2001).
R-HSA-3371360 (Reactome) Following recruitment to the DISC, FLIP(L) forms a heterodimer with caspase-8 through both death effector domain (DED) and caspase-like domain (CLD). In addition, FLIP-L can also regulate TNF-R1 signaling via interaction with the DED of FADD. The regulatory function of FLIP(L) has been found to differ depending on its expression levels. c-FLIP was shown to inhibit death receptor (DR)-mediated apoptosis only when expressed at high levels, while low cell levels of FLIP(L) enhanced DR signaling to apoptosis (Boatright KM et al. 2004; Okano H et al. 2003; Yerbes R et al. 2011). The expression levels of c-FLIP proteins were shown to be regulated by NFkappaB signaling pathway (Micheau O et a. 2001; Kreuz S et al 2001).
R-HSA-3465448 (Reactome) In the presence of FLIP(L), both caspase-8 and FLIP(L) are recruited and partially processed at the death-inducing signaling complex (DISC). The partially processed proteins stay bound to the DISC.

The long cellular FLIP (FLIP(L) or c-FLIPL) has two death effector domains (DED) and a caspase-like domain that lacks catalytic activity due to absence of a cysteine residue. Processing of FLIP(L) occurs at the DISC and depends on caspase-8 activity (zymogen and mature form). Upon activation FLIP(L) is cleaved to generate N-terminal FLIP(p43) and C-terminal FLIP(p12)(Irmler M et al. 1997; Jong WY et al. 2009). Processed FLIP(L) can enhance the proteolytic activity of procaspase-8 (Chang DW et al. 2002; Jong WY et al. 2009; Pop C et al. 2011). However, the increased FLIP(L) protein levels in cells have been found to limit caspase-8 activity and inhibit apoptotic signaling pathway,

R-HSA-3465459 (Reactome) Pro-caspase-8 and FLIP(L) are recruited to FAS/CD95 receptor complex where FLIP(L) forms a heterodimer with caspase-8 through both death effector domain (DED) and caspase-like domain (CLD). In addition, FLIP(L) can also regulate signaling via interaction with the DED of FADD. The regulatory function of FLIP(L) has been found to differ depending on its expression levels. FLIP(L) was shown to inhibit death receptor (DR)-mediated apoptosis only when expressed at high levels, while low cell levels of FLIP-L enhanced DR signaling to apoptosis (Chang DW et al. 2002; Fricker N et al. 2010; Toivonen HT et al. 2011; Boatright KM et al. 2004; Okano H et al. 2003). The expression levels of c-FLIP proteins were shown to be regulated by NFkappaB signaling pathway (Micheau O et a. 2001; Kreuz S et al 2001).
R-HSA-73945 (Reactome) Monomeric caspase-8 zymogens undergo dimerization and subsequent conformational changes at the FASL:FAS Receptor Trimer:FADD:procaspase-8 receptor complex leading to the formation of the catalytically active form of procaspase-8.
TNFSF10:TNFRSF10A,B:FADD:2xCASP8(1-479)ArrowR-HSA-141156 (Reactome)
TNFSF10:TNFRSF10A,B:FADD:CASP8(1-479):CFLARArrowR-HSA-3371359 (Reactome)
TNFSF10:TNFRSF10A,B:FADD:CASP8(1-479)R-HSA-141156 (Reactome)
TNFSF10:TNFRSF10A,B:FADD:CASP8(1-479)R-HSA-3371359 (Reactome)
TRADD:TRAF2:RIP1:FADD:CASP8(1-479)R-HSA-141159 (Reactome)
TRADD:TRAF2:RIP1:FADD:CASP8(1-479)R-HSA-3371360 (Reactome)
TRADD:TRAF2:RIP1:FADD:procaspase-8:FLIP(L)ArrowR-HSA-3371360 (Reactome)
TRAF2:TRADD:RIP1:FADD:2xCASP8(1-479)ArrowR-HSA-141159 (Reactome)
activated TLR3/TLR4:TRIF:RIP1:FADD:pro-caspase-8R-HSA-2562564 (Reactome)
activated TLR3/TLR4:TRIF:RIP1:FADD:pro-caspase-8mim-catalysisR-HSA-2562564 (Reactome)
activated TLR3/TLR4:TRIF:RIP1:FADDArrowR-HSA-2562564 (Reactome)
active caspase-8ArrowR-HSA-139952 (Reactome)
active caspase-8ArrowR-HSA-2562564 (Reactome)
active caspase-8mim-catalysisR-HSA-139952 (Reactome)
active caspase-8mim-catalysisR-HSA-3465448 (Reactome)
viral c-FLIP homologueTBarR-HSA-139952 (Reactome)

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