Tight sequestration of BH3 proteins by BCL-xL at subcellular membranes contributes to apoptotic resistance

Pécot, J. et al. (2016) Tight sequestration of BH3 proteins by BCL-xL at subcellular membranes contributes to apoptotic resistance. Cell Reports, 17(12), pp. 3347-3358. (doi: 10.1016/j.celrep.2016.11.064) (PMID:28009301)

Abstract

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.

• Item Type: Articles
• Additional Information: J.P. and C.V. are supported by PhD fellowships from the Ministe`re de la Recherche et de l’Enseignement Supe´rieur, and J.L.P. was supported by a PhD fellowship from INSERM Region. This work was supported by Re´ gion Pays de la Loire (CIMATH2), Ligue contre le Cancer (R13137), ARC (R15083NN), and INCA PLBio 2013 (R12134NN).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Bock, Dr Florian and Tait, Professor Stephen
• Authors: Pécot, J., Maillet, L., Le Pen, J., Vuillier, C., Trécesson, S. d. C., Fétiveau, A., Sarosiek, K. A., Bock, F. J., Braun, F., Letai, A., Tait, S. W.G., Gautier, F., and Juin, P. P.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell Reports
• Publisher: Elsevier (Cell Press)
• ISSN: 2211-1247
• ISSN (Online): 2211-1247
• Published Online: 22 December 2016
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in Cell Reports 17(12): 3347-3358
• Publisher Policy: Reproduced under a Creative Commons License