Caspase-10 Negatively Regulates Caspase-8-Mediated Cell Death, Switching the Response to CD95L in Favor of NF-κB Activation and Cell Survival
Open accessAbstract
Formation of the death-inducing signaling complex (DISC) initiates extrinsic apoptosis. Caspase-8 and its regulator cFLIP control death signaling by binding to death-receptor-bound FADD. By elucidating the function of the caspase-8 homolog, caspase-10, we discover that caspase-10 negatively regulates caspase-8-mediated cell death. Significantly, we reveal that caspase-10 reduces DISC association and activation of caspase-8. Furthermore, we extend our co-operative/hierarchical binding model of caspase-8/cFLIP and show that caspase-10 does not compete with caspase-8 for binding to FADD. Utilizing caspase-8-knockout cells, we demonstrate that caspase-8 is required upstream of both cFLIP and caspase-10 and that DISC formation critically depends on the scaffold function of caspase-8. We establish that caspase-10 rewires DISC signaling to NF-κB activation/cell survival and demonstrate that the catalytic activity of caspase-10, and caspase-8, is redundant in gene induction. Thus, our data are consistent with a model in which both caspase-10 and cFLIP coordinately regulate CD95L-mediated signaling for death or survival.
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Following FAS activation, CASP10 causes dissociation of CASP8 from DISC, thereby promoting cell survival.
“A recent study shows that—following FAS activation—CASP10 causes the dissociation of CASP8 from the DISC, thereby promoting cell survival [319].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [319]
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- Authors
- Horn, S., Hughes, M. A., Schilling, R., Sticht, C., Tenev, T., Ploesser, M., Meier, P., Sprick, M. R., MacFarlane, M., & Leverkus, M.
- Affiliations
- Heidelberg University (DE)
- MRC Toxicology Unit (GB)
- Institute of Cancer Research (GB)
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (DE)
- Corresponding author
- Horn, Sebastian
- Sprick, Martin R.
- MacFarlane, Marion
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 19
- Issue
- 4
- Pages
- 785-797
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5413585
- OpenAlex
- W2608218444
- Cited by
- 119
- References
- 52
- Citations by year
- 2026: 14 · 2025: 8 · 2024: 11 · 2023: 6 · 2022: 14 · 2021: 17 · 2020: 14 · 2019: 17 · 2018: 12 · 2017: 6
- FWCI
- 5.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Leicester Research Archive (University of Leicester) (submittedVersion, cc-by)
- RWTH Publications (RWTH Aachen)
- Funders
- EU Horizon 2020
- Deutsche Forschungsgemeinschaft (Le 953/6-1, 953/8-1)
- Deutsche Forschungsgemeinschaft RTG 2099
- Dietmar Hopp Foundation
- UK Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- caspase-10, caspase-8, c-FLIP, Fas ligand, FADD, death-inducing signaling complex, extrinsic apoptotic pathway, NF-κB activation, cell survival, gene induction
- MeSH terms
- NF-KappaB Inhibitor alpha, Cell Line, Cell Survival, HeLa Cells, Humans, Imidazoles, Indoles, Oligopeptides, RNA, Messenger, Signal Transduction, Interleukin-8, NF-kappa B, Apoptosis, fas Receptor, RNA Interference, RNA, Small Interfering, Caspase 8, Fas-Associated Death Domain Protein, Fas Ligand Protein, CASP8 and FADD-Like Apoptosis Regulating Protein, Caspase 10, Clustered Regularly Interspaced Short Palindromic Repeats
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