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

• Published in: Cell reports (Cambridge) 2016-12, Vol.17 (12), p.3347-3358
• Main Authors: Pécot, Jessie, Maillet, Laurent, Le Pen, Janic, Vuillier, Céline, Trécesson, Sophie de Carné, Fétiveau, Aurélie, Sarosiek, Kristopher A., Bock, Florian J., Braun, Frédérique, Letai, Anthony, Tait, Stephen W.G., Gautier, Fabien, Juin, Philippe P.
• Format: Article
• Language: English
• Subjects: Apoptosis - genetics; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Bcl-2-Like Protein 11 - genetics; bcl-X Protein - genetics; bcl-X Protein - metabolism; BCL-xL; BH3 mimetic resistance; Cancer; Cell Survival - genetics; Cell-Free System; HCT116 Cells; Humans; Life Sciences; membrane localization; Mitochondria - genetics; Mitochondria - metabolism; Neoplasms - drug therapy; Neoplasms - genetics; Peptide Fragments - administration & dosage; Proto-Oncogene Proteins - administration & dosage; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-bcl-2 - genetics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.11.064

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. [Display omitted] •BH3 mimetics inefficiently derepress BCL-xL inhibition of PUMA-induced BAX activation•BH3 mimetics do not target all intracellular BCL-xL complexes equally well•Membrane binding of BCL-xL contributes to BH3 mimetic resistance Pécot et al. show that sequestration of pro-apoptotic proteins by BCL-xL is favored by its membrane binding and low level mitochondrial translocation dynamics. This explains why membrane-localized BCL-xL has enhanced anti-apoptotic properties and establishes that intracellular localization of BCL-xL, per se, is critical for cell survival regulation.