ArticleMolecular cell2012
A death effector domain chain DISC model reveals a crucial role for caspase-8 chain assembly in mediating apoptotic cell death.
Article in Molecular cell, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 182 papers.
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Who cites it
182 citing papers in PubMed, 331 citations in OpenAlex.
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- Sublethal Caspase-8 Activation Drives Radiation-Induced Genetic Instability and Oncogenic Transformation Through Endonuclease G and Non-Canonical NF-κB Signaling.International journal of molecular sciences · 2026Article
- Beyond biochemical cascades: the biophysical execution of disulfidptosis via actin network collapse.Molecular biology reports · 2026Review
- Extrinsic apoptosis and necroptosis in telencephalic development: a single-cell mass cytometry study.Cell death and differentiation · 2026Article
- The role of different types of programmed cell death in myocardial fibrosis: from mechanisms to therapeutics.Frontiers in cardiovascular medicine · 2026Review
- Decoding necrosome assembly: harmonizing signal amplification and attenuation through optimal RIP3 stoichiometry.Nature communications · 2025Article
- Obligate intracellular bacteria and host cell death pathways-the matter of life and death.Cell and tissue research · 2025Review
- Mammalian innate antiviral defenses: beyond interferon.Journal of virology · 2025Review
- Large transient assemblies of Apaf1 constitute the apoptosome in cells.Nature communications · 2025Article
- CD95/Fas stoichiometry in future precision medicine.Cell death and differentiation · 2025Review
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- Deep transfer learning approach for automated cell death classification reveals novel ferroptosis-inducing agents in subsets of B-ALL.Cell death & disease · 2025Article
- Fungal Als proteins hijack host death effector domains to promote inflammasome signaling.Nature communications · 2025Article
- Review
- Pharmacological targeting of caspase-8/c-FLIPCommunications biology · 2025Article
- Serum periostin as a novel biomarker and therapeutic target in coronary heart disease.Frontiers in cardiovascular medicine · 2025Article
- Biological Functions and Clinical Implications of CFLAR: From Cell Death Mechanisms to Therapeutic Targeting in Immune Regulation.Journal of inflammation research · 2025Review
- Dissecting caspase-2-mediated cell death: from intrinsic PIDDosome activation to chemical modulation.Protein & cell · 2024Article
- Pro-apoptotic and anti-proliferative activities of cassane diterpenoids on squamous carcinoma cells: An in vitro and in silico study.Toxicology reports · 2024Article
122 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.