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Cell Rep. 2017 Apr 25;19(4):785-797. doi: 10.1016/j.celrep.2017.04.010.

Caspase-10 Negatively Regulates Caspase-8-Mediated Cell Death, Switching the Response to CD95L in Favor of NF-κB Activation and Cell Survival.

Author information

1
Section of Molecular Dermatology, Department of Dermatology, Venereology, and Allergology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. Electronic address: sebastian-horn@gmx.net.
2
MRC Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK.
3
Section of Molecular Dermatology, Department of Dermatology, Venereology, and Allergology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
4
Center for Medical Research, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
5
The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, Mary-Jean Mitchell Green Building, Chester Beatty Laboratories, Fulham Road, London SW3 6JB, UK.
6
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: m.sprick@dkfz-heidelberg.de.
7
MRC Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK. Electronic address: mm21@leicester.ac.uk.
8
Section of Molecular Dermatology, Department of Dermatology, Venereology, and Allergology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; Department of Dermatology and Allergology, Medical Faculty of the RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany.

Abstract

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.

KEYWORDS:

CD95; DISC; NF-κB; cFLIP; caspase-10; caspase-8; cell death

PMID:
28445729
PMCID:
PMC5413585
DOI:
10.1016/j.celrep.2017.04.010
[Indexed for MEDLINE]
Free PMC Article

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