Caspase-10 Negatively Regulates Caspase-8-Mediated Cell Death, Switching the Response to CD95L in Favor of NF-κB Activation and Cell Survival
Sebastian Horn,
Michelle A. Hughes,
Ramon Schilling,
Carsten Sticht,
Tencho Tenev,
Michaela Ploesser,
Pascal Meier,
Martin R. Sprick,
Marion MacFarlane,
Martin Leverkus
Affiliations
Sebastian Horn
Section of Molecular Dermatology, Department of Dermatology, Venereology, and Allergology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
Michelle A. Hughes
MRC Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK
Ramon Schilling
Section of Molecular Dermatology, Department of Dermatology, Venereology, and Allergology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
Carsten Sticht
Center for Medical Research, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
Tencho Tenev
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
Michaela Ploesser
Section of Molecular Dermatology, Department of Dermatology, Venereology, and Allergology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
Pascal Meier
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
Martin R. Sprick
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Marion MacFarlane
MRC Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Road, Leicester LE1 9HN, UK
Martin Leverkus
Section of Molecular Dermatology, Department of Dermatology, Venereology, and Allergology, Medical Faculty Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
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.
