A Death Effector Domain Chain DISC Model Reveals a Crucial Role for Caspase-8 Chain Assembly in Mediating Apoptotic Cell Death
Open accessAbstract
Formation of the death-inducing signaling complex (DISC) is a critical step in death receptor-mediated apoptosis, yet the mechanisms underlying assembly of this key multiprotein complex remain unclear. Using quantitative mass spectrometry, we have delineated the stoichiometry of the native TRAIL DISC. While current models suggest that core DISC components are present at a ratio of 1:1, our data indicate that FADD is substoichiometric relative to TRAIL-Rs or DED-only proteins; strikingly, there is up to 9-fold more caspase-8 than FADD in the DISC. Using structural modeling, we propose an alternative DISC model in which procaspase-8 molecules interact sequentially, via their DED domains, to form a caspase-activating chain. Mutating key interacting residues in procaspase-8 DED2 abrogates DED chain formation in cells and disrupts TRAIL/CD95 DISC-mediated procaspase-8 activation in a functional DISC reconstitution model. This provides direct experimental evidence for a DISC model in which DED chain assembly drives caspase-8 dimerization/activation, thereby triggering cell death.
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CASP8 maturation involves a cascade initiated by binding of CASP8 to FADD at DISC.
“In particular, CASP8 maturation involves a cascade of events initiated by the binding of CASP8 to FADD at the DISC.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [292]
Binding of CASP8 to FADD enables assembly of a linear filament of CASP8 molecules that facilitates homodimerization and activation by autoproteolytic cleavage.
“This interaction enables the assembly of a linear filament of CASP8 molecules (depending on their DEDs) that facilitates homodimerization and consequent activation by autoproteolytic cleavage [291–295].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [292]
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References 59 · Cited by 349
- Authors
- Dickens, L. S., Boyd, R. S., Jukes-Jones, R., Hughes, M. A., Robinson, G. L., Fairall, L., Schwabe, J. W. R., Cain, K., & MacFarlane, M.
- Affiliations
- MRC Toxicology Unit (GB)
- University of Leicester (GB)
- Corresponding author
- Cain, Kelvin
- MacFarlane, Marion
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2012-07
- Volume
- 47
- Issue
- 2
- Pages
- 291-305
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3477315
- OpenAlex
- W2089909793
- Cited by
- 349
- References
- 59
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 23 · 2023: 11 · 2022: 26 · 2021: 29 · 2020: 30 · 2019: 25 · 2018: 31 · 2017: 29 · 2016: 28 · 2015: 34 · 2014: 28 · 2013: 19 · 2012: 4
- FWCI
- 10.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- death-inducing signaling complex, caspase-8, death effector domain, TRAIL, FADD, death receptor signaling, apoptosis, Fas
- MeSH terms
- Enzyme Activation, HeLa Cells, Humans, Models, Biological, Models, Molecular, Molecular Conformation, Mass Spectrometry, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Apoptosis, fas Receptor, Jurkat Cells, Cell Line, Tumor, Caspase 8, Receptors, TNF-Related Apoptosis-Inducing Ligand, Death Domain Receptor Signaling Adaptor Proteins
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