Molecular architecture of the DED chains at the DISC: regulation of procaspase-8 activation by short DED proteins c-FLIP and procaspase-8 prodomain
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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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Elevated expression levels of c-FLIPL inhibit, rather than activate, extrinsic apoptosis possibly by disrupting CASP8 maturation.
“supporting the notion that elevated expression levels of c-FLIPL inhibit, rather than activate, extrinsic apoptosis possibly by disrupting CASP8 maturation [301, 304].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [304]
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- Authors
- Schleich, K., Buchbinder, J. H., Pietkiewicz, S., Kähne, T., Warnken, U., Öztürk, S., Schnölzer, M., Naumann, M., Krammer, P. H., & Lavrik, I. N.
- Affiliations
- German Cancer Research Center (DE)
- Otto-von-Guericke-Universität Magdeburg (DE)
- Institute of Cytology and Genetics (RU)
- Corresponding author
- Lavrik, I N
- Venue
- Cell Death & Differentiation
- Published
- 2015-10-23
- Volume
- 23
- Issue
- 4
- Pages
- 681-694
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC4986640
- OpenAlex
- W2121837861
- Cited by
- 86
- References
- 52
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 10 · 2023: 4 · 2022: 10 · 2021: 12 · 2020: 11 · 2019: 8 · 2018: 7 · 2017: 8 · 2016: 7 · 2015: 1
- FWCI
- 3.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cell Death and Differentiation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bundesministerium für Bildung und Forschung
- 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, death effector domain, c-FLIP, negative feedback loop, FADD, heterodimer formation
- MeSH terms
- Protein Domains, Cell Line, Enzyme Activation, Humans, Apoptosis, fas Receptor, Caspase 8, CASP8 and FADD-Like Apoptosis Regulating Protein
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