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

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

  • Cell Rep. 2017 Apr 25;19(4):785-797. doi: 10.1016/j.celrep.2017.04.010.
Sebastian Horn 1,  Michelle A Hughes 2,  Ramon Schilling 3,  Carsten Sticht 4,  Tencho Tenev 5,  Michaela Ploesser 3,  Pascal Meier 5,  Martin R Sprick 6,  Marion MacFarlane 7,  Martin Leverkus 8
Affiliations

Affiliations

  • 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: [email protected].
  • 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: [email protected].
  • 7 MRC Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK. Electronic address: [email protected].
  • 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.
PMID: 28445729 DOI: 10.1016/j.celrep.2017.04.010
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.

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