Tight Sequestration of BH3 Proteins by BCL-xL at Subcellular Membranes Contributes to Apoptotic Resistance.

Autor:	Pécot J; CRCNA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44035 Nantes, France., Maillet L; CRCNA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44035 Nantes, France., Le Pen J; CRCNA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44035 Nantes, France., Vuillier C; CRCNA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44035 Nantes, France., Trécesson SC; CRCNA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44035 Nantes, France., Fétiveau A; CRCNA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44035 Nantes, France., Sarosiek KA; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., Bock FJ; Cancer Research UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK., Braun F; CRCNA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44035 Nantes, France., Letai A; Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA., Tait SWG; Cancer Research UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK., Gautier F; CRCNA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44035 Nantes, France; ICO René Gauducheau, 44805 Saint Herblain, France. Electronic address: fabien.gautier@univ-nantes.fr., Juin PP; CRCNA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44035 Nantes, France; ICO René Gauducheau, 44805 Saint Herblain, France. Electronic address: philippe.juin@univ-nantes.fr.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2016 Dec 20; Vol. 17 (12), pp. 3347-3358.
DOI:	10.1016/j.celrep.2016.11.064
Abstrakt:	Anti-apoptotic BCL-2 family members bind to BH3-only proteins and multidomain BAX/BAK to preserve mitochondrial integrity and maintain survival. Whereas inhibition of these interactions is the biological basis of BH3-mimetic anti-cancer therapy, the actual response of membrane-bound protein complexes to these compounds is currently ill-defined. Here, we find that treatment with BH3 mimetics targeting BCL-xL spares subsets of cells with the highest levels of this protein. In intact cells, sequestration of some pro-apoptotic activators (including PUMA and BIM) by full-length BCL-xL is much more resistant to derepression than previously described in cell-free systems. Alterations in the BCL-xL C-terminal anchor that impacts subcellular membrane-targeting and localization dynamics restore sensitivity. Thus, the membrane localization of BCL-xL enforces its control over cell survival and, importantly, limits the pro-apoptotic effects of BH3 mimetics by selectively influencing BCL-xL binding to key pro-apoptotic effectors. (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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