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].
View original pathway at Reactome.</div>
Kataoka T, Budd RC, Holler N, Thome M, Martinon F, Irmler M, Burns K, Hahne M, Kennedy N, Kovacsovics M, Tschopp J.; ''The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways.''; PubMedEurope PMCScholia
Harper N, Hughes M, MacFarlane M, Cohen GM.; ''Fas-associated death domain protein and caspase-8 are not recruited to the tumor necrosis factor receptor 1 signaling complex during tumor necrosis factor-induced apoptosis.''; PubMedEurope PMCScholia
Gangloff M, Gay NJ.; ''MD-2: the Toll 'gatekeeper' in endotoxin signalling.''; PubMedEurope PMCScholia
Micheau O, Thome M, Schneider P, Holler N, Tschopp J, Nicholson DW, Briand C, Grütter MG.; ''The long form of FLIP is an activator of caspase-8 at the Fas death-inducing signaling complex.''; PubMedEurope PMCScholia
Sprick MR, Weigand MA, Rieser E, Rauch CT, Juo P, Blenis J, Krammer PH, Walczak H.; ''FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2.''; PubMedEurope PMCScholia
Cusson-Hermance N, Khurana S, Lee TH, Fitzgerald KA, Kelliher MA.; ''Rip1 mediates the Trif-dependent toll-like receptor 3- and 4-induced NF-{kappa}B activation but does not contribute to interferon regulatory factor 3 activation.''; PubMedEurope PMCScholia
Chang DW, Xing Z, Capacio VL, Peter ME, Peter ME, Yang X.; ''Interdimer processing mechanism of procaspase-8 activation.''; PubMedEurope PMCScholia
Pop C, Oberst A, Drag M, Van Raam BJ, Riedl SJ, Green DR, Salvesen GS.; ''FLIP(L) induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity.''; PubMedEurope PMCScholia
Hughes MA, Harper N, Butterworth M, Cain K, Cohen GM, MacFarlane M.; ''Reconstitution of the death-inducing signaling complex reveals a substrate switch that determines CD95-mediated death or survival.''; PubMedEurope PMCScholia
Vittori D, Vota D, Callero M, Chamorro ME, Nesse A.; ''c-FLIP is involved in erythropoietin-mediated protection of erythroid-differentiated cells from TNF-alpha-induced apoptosis.''; PubMedEurope PMCScholia
Blanchard H, Kodandapani L, Mittl PR, Marco SD, Krebs JF, Wu JC, Tomaselli KJ, Grütter MG.; ''The three-dimensional structure of caspase-8: an initiator enzyme in apoptosis.''; PubMedEurope PMCScholia
Scaffidi C, Schmitz I, Krammer PH, Peter ME.; ''The role of c-FLIP in modulation of CD95-induced apoptosis.''; PubMedEurope PMCScholia
Kohlhaas SL, Craxton A, Sun XM, Pinkoski MJ, Cohen GM.; ''Receptor-mediated endocytosis is not required for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis.''; PubMedEurope PMCScholia
Fricker N, Beaudouin J, Richter P, Eils R, Krammer PH, Lavrik IN.; ''Model-based dissection of CD95 signaling dynamics reveals both a pro- and antiapoptotic role of c-FLIPL.''; PubMedEurope PMCScholia
Seal S, Hockenbery DM, Spaulding EY, Kiem HP, Abbassi N, Deeg HJ.; ''Differential responses of FLIPLong and FLIPShort-overexpressing human myeloid leukemia cells to TNF-alpha and TRAIL-initiated apoptotic signals.''; PubMedEurope PMCScholia
Keller N, Mares J, Zerbe O, Grütter MG.; ''Structural and biochemical studies on procaspase-8: new insights on initiator caspase activation.''; PubMedEurope PMCScholia
Yerbes R, Palacios C, Reginato MJ, López-Rivas A.; ''Cellular FLIP(L) plays a survival role and regulates morphogenesis in breast epithelial cells.''; PubMedEurope PMCScholia
Chinnaiyan AM, O'Rourke K, Tewari M, Dixit VM.; ''FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis.''; PubMedEurope PMCScholia
Keller N, Grütter MG, Zerbe O.; ''Studies of the molecular mechanism of caspase-8 activation by solution NMR.''; PubMedEurope PMCScholia
Wang L, Du F, Wang X.; ''TNF-alpha induces two distinct caspase-8 activation pathways.''; PubMedEurope PMCScholia
Feoktistova M, Geserick P, Kellert B, Dimitrova DP, Langlais C, Hupe M, Cain K, MacFarlane M, Häcker G, Leverkus M.; ''cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms.''; PubMedEurope PMCScholia
Donepudi M, Mac Sweeney A, Briand C, Grütter MG.; ''Insights into the regulatory mechanism for caspase-8 activation.''; PubMedEurope PMCScholia
Watt W, Koeplinger KA, Mildner AM, Heinrikson RL, Tomasselli AG, Watenpaugh KD.; ''The atomic-resolution structure of human caspase-8, a key activator of apoptosis.''; PubMedEurope PMCScholia
Kreuz S, Siegmund D, Rumpf JJ, Samel D, Leverkus M, Janssen O, Häcker G, Dittrich-Breiholz O, Kracht M, Scheurich P, Wajant H.; ''NFkappaB activation by Fas is mediated through FADD, caspase-8, and RIP and is inhibited by FLIP.''; PubMedEurope PMCScholia
Siegmund D, Mauri D, Peters N, Juo P, Thome M, Reichwein M, Blenis J, Scheurich P, Tschopp J, Wajant H.; ''Fas-associated death domain protein (FADD) and caspase-8 mediate up-regulation of c-Fos by Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) via a FLICE inhibitory protein (FLIP)-regulated pathway.''; PubMedEurope PMCScholia
Ashkenazi A, Dixit VM.; ''Death receptors: signaling and modulation.''; PubMedEurope PMCScholia
Oberst A, Pop C, Tremblay AG, Blais V, Denault JB, Salvesen GS, Green DR.; ''Inducible dimerization and inducible cleavage reveal a requirement for both processes in caspase-8 activation.''; PubMedEurope PMCScholia
Kataoka T, Tschopp J.; ''N-terminal fragment of c-FLIP(L) processed by caspase 8 specifically interacts with TRAF2 and induces activation of the NF-kappaB signaling pathway.''; PubMedEurope PMCScholia
Kalai M, Van Loo G, Vanden Berghe T, Meeus A, Burm W, Saelens X, Vandenabeele P.; ''Tipping the balance between necrosis and apoptosis in human and murine cells treated with interferon and dsRNA.''; PubMedEurope PMCScholia
Boatright KM, Renatus M, Scott FL, Sperandio S, Shin H, Pedersen IM, Ricci JE, Edris WA, Sutherlin DP, Green DR, Salvesen GS.; ''A unified model for apical caspase activation.''; PubMedEurope PMCScholia
Kaiser WJ, Offermann MK.; ''Apoptosis induced by the toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motif.''; PubMedEurope PMCScholia
Micheau O, Tschopp J.; ''Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes.''; PubMedEurope PMCScholia
Yu JW, Jeffrey PD, Shi Y.; ''Mechanism of procaspase-8 activation by c-FLIPL.''; PubMedEurope PMCScholia
Sharma V, Tewari R, Sk UH, Joseph C, Sen E.; ''Ebselen sensitizes glioblastoma cells to Tumor Necrosis Factor (TNFalpha)-induced apoptosis through two distinct pathways involving NF-kappaB downregulation and Fas-mediated formation of death inducing signaling complex.''; PubMedEurope PMCScholia
Rushworth SA, Taylor A, Langa S, MacEwan DJ.; ''TNF signaling gets FLIPped off: TNF-induced regulation of FLIP.''; PubMedEurope PMCScholia
Sharp DA, Lawrence DA, Ashkenazi A.; ''Selective knockdown of the long variant of cellular FLICE inhibitory protein augments death receptor-mediated caspase-8 activation and apoptosis.''; PubMedEurope PMCScholia
The death receptors (DR), all cell-surface receptors, that belong to the TNF receptor superfamily (TNFRSF). The term death receptor refers to those members of the TNFRSF that contain a "death domain" (DD) within their cytoplasmic tail which provides the capacity for protein–protein interactions with other DD-containing proteins suach as FADD. The main signals transmitted from TNF death receptors such as TNFR1, TRAIL-R, and CD95/FAS in response to their cognate ligand binding result in an apoptotic signaling pathway characterized by direct activation of intracellular cysteine proteases (caspases), without directly involving the mitochondrial death pathway. However, these death receptors have also been shown to initiate survival signals via the activation of transcription factors NFκappaB and AP1. This project describes an assembly of the death-inducing signaling complex (DISC) downstream of TNFR1, TRAIL-R, and CD95/FAS and shows protein composition and stoichiometry within the DISC. 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. The project also describes neuron-type-specific signaling by the p75NTR death receptor (also known as NGFR) that can regulate a number of different biological activities in response to ligand binding, including cell death and/or survival, axonal growth and synaptic plasticity.
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.
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].
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.
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.
TLR4 and TLR3 signaling pathways 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].
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).
Following recruitment to the death-inducing signaling complex (DISC) and called complex II in the TNFR1 signalling pathway, cellular FLICE-like inhibitory protein (cFLIP) forms a heterodimer with procaspase-8. The presence of cFLIP in complex II determines if and how cells die. cFLIP is encoded by the CFLAR gene and is expressed in two major isoforms cFLIP long (FLIP(L)) and cFLIP short (FLIP(S)). While both FLIP(L) and FLIP(S) form heterodimers with procaspase-8, they differentially control caspase-8 activation. FLIP(L) interacts with procaspase-8 through both death effector domain (DED) and caspase-like domain (CLD). The procaspase-8 catalytic domain prefers heterodimerization with the CLD of FLIP(L) over homodimerization with catalytic domains of other procaspase-8 molecules (Boatright KM et al. 2004; Yu JW et al. 2009). Heterodimerization to FLIP(L) rearranges the catalytic site of procaspase-8, producing a conformation that renders the heterodimer highly active even in the absence of proteolytic processing of either caspase-8 or cFLIPL (Micheau O et al. 2002; Yu JW et al. 2009; reviewed in Tummers B & Green DR 2017). In addition, FLIP(L) can also regulate TNFR1 signaling via interaction with the DED of FADD (Majkut J et al. 2014). However, other studies showed that FLIP(L) is only weakly able to bind FADD (Hughes MA et al. 2016; Fu TM et al. 2016; Schleich K et al. 2016), 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 (Boatright KM et al. 2004; Okano H et al. 2003; Yerbes R et al. 2011; Hughes MA et al. 2016). The FLIP(S) protein lacks CLD and contains only two tandem DEDs and a short C-terminal tail. FLIP(S) blocks DISC-dependent procaspase-8 activation. The expression levels of cFLIP proteins were shown to be regulated by NFkappaB signaling pathway (Micheau O et a. 2001; Kreuz S et al 2001).
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,
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).
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.
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DataNodes
Receptor
Trimer:FADD:pro-Caspase-8:FLIP(L)receptor
trimer:FADD:procaspase-8-dimerTRIF recruitment to TLR complex stimulates distinct pathways leading to production of type 1 interferons (IFNs), pro-inflammatory cytokines and induction of programmed cell death.
Annotated Interactions
Receptor
Trimer:FADD:pro-Caspase-8:FLIP(L)receptor
trimer:FADD:procaspase-8-dimerThe 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,