Reactome | Caspase-8 processing within TLR4 complex

Caspase-8 processing within TLR4 complex

Stable Identifier

R-HSA-2562564

Type

Reaction [transition]

Species

Homo sapiens

Compartment

endosome membrane, cytosol

ReviewStatus

5/5

Locations in the PathwayBrowser

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Immune System (Homo sapiens)

- Innate Immune System (Homo sapiens)
  - Toll-like Receptor Cascades (Homo sapiens)
    - Toll Like Receptor 4 (TLR4) Cascade (Homo sapiens)
      - MyD88-independent TLR4 cascade (Homo sapiens)
        
        TRIF (TICAM1)-mediated TLR4 signaling (Homo sapiens)
        
        TRIF-mediated programmed cell death (Homo sapiens)
        
        Caspase-8 processing within TLR4 complex (Homo sapiens)

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Caspase-8 processing within TLR4 complex

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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].

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
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