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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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journal contribution
posted on 15.07.2019, 11:28 by S Horn, MA Hughes, R Schilling, C Sticht, T Tenev, M Ploesser, P Meier, MR Sprick, M MacFarlane, M Leverkus
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.

Funding

Work in the laboratory of M.L. was funded by EU Horizon 2020 (MelPlex ESR network; project 5) and grants of the Deutsche Forschungsgemeinschaft (Le 953/6-1 and 953/8-1). M.L. was supported by Deutsche Forschungsgemeinschaft RTG 2099 (projects 9 and 10). Project 9 supports R.S., and project 10 provides funding for S.H. M.R.S. is supported by the Dietmar Hopp Foundation. M.M. and M.A.H. are supported by the UK Medical Research Council.

History

Citation

Cell Reports, 19 (4), pp. 785-797

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Molecular & Cell Biology

Version

VoR (Version of Record)

Published in

Cell Reports

Publisher

Elsevier

eissn

2211-1247

Acceptance date

03/04/2017

Copyright date

2017

Available date

15/07/2019

Notes

The accession number for the microarray dataset reported in this paper is GEO: GSE75365. Supplementary information is available to download from the publisher's website at https://doi.org/10.1016/j.celrep.2017.04.010

Language

en