Caspase-8 processing within TLR3 complex

Stable Identifier
Reaction [transition]
Homo sapiens
Related Species
Influenza A virus, Rotavirus, Hepatitis B virus, Hepatitis C Virus, Human herpesvirus 1
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TLR3 and TLR4 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).
Literature References
PubMed ID Title Journal Year
19278658 Structural and biochemical studies on procaspase-8: new insights on initiator caspase activation

Zerbe, O, Keller, N, Grütter, MG, Mares, J

Structure 2009
15814722 Apoptosis induced by the toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motif

Offermann, MK, Kaiser, WJ

J Immunol 2005
22421964 dsRNA induces apoptosis through an atypical death complex associating TLR3 to caspase-8

Pierrot, A, Salaun, B, Lalaoui, N, Jacquemin, G, Micheau, O, Renno, T, Bonnin, M, Vanbervliet, B, Virard, F, Estornes, Y, Lebecque, S, Pachéco, Y, Toscano, F, Mercier-Gouy, P

Cell Death Differ. 2012
20308068 Inducible dimerization and inducible cleavage reveal a requirement for both processes in caspase-8 activation

Blais, V, Oberst, A, Denault, JB, Green, DR, Salvesen, GS, Tremblay, AG, Pop, C

J Biol Chem 2010
12620240 Insights into the regulatory mechanism for caspase-8 activation

Grütter, MG, Briand, C, Mac Sweeney, A, Donepudi, M

Mol. Cell 2003
12181749 Tipping the balance between necrosis and apoptosis in human and murine cells treated with interferon and dsRNA

Kalai, M, Van Loo, G, Vandenabeele, P, Burm, W, Meeus, A, Vanden Berghe, T, Saelens, X

Cell Death Differ. 2002
21737330 cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms

Langlais, C, Geserick, P, Kellert, B, Häcker, G, Cain, K, Feoktistova, M, Hupe, M, MacFarlane, M, Leverkus, M, Dimitrova, DP

Mol. Cell 2011
Event Information
Catalyst Activity

cysteine-type endopeptidase activity of activated TLR3:TRIF:RIP1:FADD:pro-caspase-8 [endosome membrane]

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