Cited by 86Cell death mechanisms and regulationCancer-related Molecular PathwaysNF-κB Signaling Pathways

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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Schleich, K, Buchbinder, J H, Pietkiewicz, S, Kähne, T, Warnken, U, Öztürk, S, Schnölzer, M, Naumann, M +2 more·2016·Cell Death & Differentiation

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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  1. Yu JW, Jeffrey PD, Shi Y. Mechanism of procaspase-8 activation by c-FLIPL. Proc Natl Acad Sci USA 2009; 106: 8169-8174.

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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
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
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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