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

Publication date: 25 April 2017
Source:Cell Reports, Volume 19, Issue 4
Author(s): Sebastian Horn, Michelle A. Hughes, Ramon Schilling, Carsten Sticht, Tencho Tenev, Michaela Ploesser, Pascal Meier, Martin R. Sprick, Marion MacFarlane, Martin 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.

Graphical abstract

Teaser

It has been assumed that caspase-10, and its homolog caspase-8, have redundant functions in cell death signaling. Horn et al. now reveal a role for caspase-10 in switching CD95 signaling from caspase-8-induced cell death to NF-κB activation/cell survival. DISC recruitment of caspase-10 and NF-κB activation critically depend upon caspase-8 scaffold function.


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