Caspase-10 Negatively Regulates Caspase-8-Mediated Cell Death, Switching the Response to CD95L in Favor of NF-κB Activation and Cell Survival.
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Date
2017-04-25ICR Author
Author
Horn, S
Hughes, MA
Schilling, R
Sticht, C
Tenev, T
Ploesser, M
Meier, P
Sprick, MR
MacFarlane, M
Leverkus, M
Type
Journal Article
Metadata
Show full item recordAbstract
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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Subject
Cell Line
Hela Cells
Humans
Imidazoles
Indoles
Oligopeptides
NF-kappa B
RNA, Small Interfering
RNA, Messenger
Interleukin-8
Signal Transduction
Apoptosis
Cell Survival
RNA Interference
Caspase 8
CASP8 and FADD-Like Apoptosis Regulating Protein
Fas Ligand Protein
Fas-Associated Death Domain Protein
Caspase 10
Clustered Regularly Interspaced Short Palindromic Repeats
NF-KappaB Inhibitor alpha
fas Receptor
Research team
Cell Death and Immunity
Language
eng
Date accepted
2017-04-03
License start date
2017-04
Citation
Cell reports, 2017, 19 (4), pp. 785 - 797
Publisher
CELL PRESS