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].
Zerbe, O, Keller, N, Grütter, MG, Mares, J
Offermann, MK, Kaiser, WJ
Blais, V, Oberst, A, Denault, JB, Green, DR, Salvesen, GS, Tremblay, AG, Pop, C
Grütter, MG, Briand, C, Mac Sweeney, A, Donepudi, M
Kalai, M, Van Loo, G, Vandenabeele, P, Burm, W, Meeus, A, Vanden Berghe, T, Saelens, X
Langlais, C, Geserick, P, Kellert, B, Häcker, G, Cain, K, Feoktistova, M, Hupe, M, MacFarlane, M, Leverkus, M, Dimitrova, DP
cysteine-type endopeptidase activity of activated TLR4:TRIF:RIP1:FADD:pro-caspase-8 [endosome membrane]
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