ArticleCell death and differentiation2016
Molecular architecture of the DED chains at the DISC: regulation of procaspase-8 activation by short DED proteins c-FLIP and procaspase-8 prodomain.
Article in Cell death and differentiation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 77 citations in OpenAlex.
- A Noncanonical Model of DED1 Interaction Betweenc-FLIPThe protein journal · 2026Article
- TIPIN coordinates ATM-dependent checkpoint and NF-κB signaling to counteract DNA replication damage from topoisomerase inhibition.Communications biology · 2025Article
- FAS mediates apoptosis, inflammation, and treatment of pathogen infection.Frontiers in cellular and infection microbiology · 2025Review
- Biological Functions and Clinical Implications of CFLAR: From Cell Death Mechanisms to Therapeutic Targeting in Immune Regulation.Journal of inflammation research · 2025Review
- Review
- Caspase-8 in inflammatory diseases: a potential therapeutic target.Cellular & molecular biology letters · 2024Review
- Arginine methylation of caspase-8 controls life/death decisions in extrinsic apoptotic networks.Oncogene · 2024Article
- A Comprehensive Exploration of Caspase Detection Methods: From Classical Approaches to Cutting-Edge Innovations.International journal of molecular sciences · 2024Review
- MYC Oncogene: A Druggable Target for Treating Cancers with Natural Products.Aging and disease · 2024Review
- Targeting caspase-8: a new strategy for combating hepatocellular carcinoma.Frontiers in immunology · 2024Review
- A rare immunological disease, caspase 8 deficiency: case report and literature review.Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology · 2023Article
- Primary and Secondary micro-RNA Modulation the Extrinsic Pathway of Apoptosis in Hepatocellular Carcinoma.Molecular biology · 2023Article
- Review
- Anti-Apoptotic c-FLIP Reduces the Anti-Tumour Activity of Chimeric Antigen Receptor T Cells.Cancers · 2022Article
- Article
- Programming inflammatory cell death for therapy.Pharmacology & therapeutics · 2022Review
- Therapeutic approaches targeting CD95L/CD95 signaling in cancer and autoimmune diseases.Cell death & disease · 2022Review
- An engineered construct of cFLIP provides insight into DED1 structure and interactions.Structure (London, England : 1993) · 2022Article
- The dual role of the CD95 and CD95L signaling pathway in glioblastoma.Frontiers in immunology · 2022Review
- MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies.Journal of hematology & oncology · 2021Review
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The CD95/Fas/APO-1 death-inducing signaling complex (DISC), comprising CD95, FADD, procaspase-8, procaspase-10, and c-FLIP, has a key role in apoptosis induction. Recently, it was demonstrated that procaspase-8 activation is driven by death effector domain (DED) chains at the DISC. Here, we analyzed the molecular architecture of the chains and the role of the short DED proteins in regulating procaspase-8 activation in the chain model. We demonstrate that the DED chains are largely composed of procaspase-8 cleavage products and, in particular, of its prodomain. The DED chain also comprises c-FLIP and procaspase-10 that are present in 10 times lower amounts compared with procaspase-8. We show that short c-FLIP isoforms can inhibit CD95-induced cell death upon overexpression, likely by forming inactive heterodimers with procaspase-8. Furthermore, we have addressed mechanisms of the termination of chain elongation using experimental and mathematical modeling approaches. We show that neither c-FLIP nor procaspase-8 prodomain terminates the DED chain, but rather the dissociation/association rates of procaspase-8 define the stability of the chain and thereby its length. In addition, we provide evidence that procaspase-8 prodomain generated at the DISC constitutes a negative feedback loop in procaspase-8 activation. Overall, these findings provide new insights into caspase-8 activation in DED chains and apoptosis initiation.
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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.