Dissecting DISC regulation via pharmacological targeting of caspase-8/c-FLIPL heterodimer
- 20 January 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Differentiation
- Vol. 27 (7), 2117-2130
- https://doi.org/10.1038/s41418-020-0489-0
Abstract
Pharmacological targeting via small molecule-based chemical probes has recently acquired an emerging importance as a valuable tool to delineate molecular mechanisms. Induction of apoptosis via CD95/Fas and TRAIL-R1/2 is triggered by the formation of the death-inducing signaling complex (DISC). Caspase-8 activation at the DISC is largely controlled by c-FLIP proteins. However molecular mechanisms of this control have just started to be uncovered. In this study we report the first-in-class chemical probe targeting c-FLIPL in the heterodimer caspase-8/c-FLIPL. This rationally designed small molecule was aimed to imitate the closed conformation of the caspase-8 L2′ loop and thereby increase caspase-8 activity after initial processing of the heterodimer. In accordance with in silico predictions, this small molecule enhanced caspase-8 activity at the DISC, CD95L/TRAIL-induced caspase activation, and subsequent apoptosis. The generated computational model provided further evidence for the proposed effects of the small molecule on the heterodimer caspase-8/c-FLIPL. In particular, the model has demonstrated that boosting caspase-8 activity by the small molecule at the early time points after DISC assembly is crucial for promoting apoptosis induction. Taken together, our study allowed to target the heterodimer caspase-8/c-FLIPL and get new insights into molecular mechanisms of its activation.This publication has 40 references indexed in Scilit:
- Cryo-EM Structure of Caspase-8 Tandem DED Filament Reveals Assembly and Regulation Mechanisms of the Death-Inducing Signaling ComplexMolecular Cell, 2016
- Stoichiometry of the CD95 Death-Inducing Signaling Complex: Experimental and Modeling Evidence for a Death Effector Domain Chain ModelMolecular Cell, 2012
- A Death Effector Domain Chain DISC Model Reveals a Crucial Role for Caspase-8 Chain Assembly in Mediating Apoptotic Cell DeathMolecular Cell, 2012
- Cellular FLICE-like inhibitory proteins (c-FLIPs): Fine-tuners of life and death decisionsExperimental Cell Research, 2012
- Regulation of CD95/Fas signaling at the DISCCell Death & Differentiation, 2011
- Reconstitution of the Death-Inducing Signaling Complex Reveals a Substrate Switch that Determines CD95-Mediated Death or SurvivalMolecular Cell, 2009
- A New C-Terminal Cleavage Product of Procaspase-8, p30, Defines an Alternative Pathway of Procaspase-8 ActivationMolecular and Cellular Biology, 2009
- Mechanism of procaspase-8 activation by c-FLIP LProceedings of the National Academy of Sciences of the United States of America, 2009
- Life and death in peripheral T cellsNature Reviews Immunology, 2007
- The role of CAP3 in CD95 signaling: new insights into the mechanism of procaspase-8 activationCell Death & Differentiation, 2005