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

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Pécot, Jessie | Maillet, Laurent, A | Le Pen, Janic, P | Vuillier, Céline | de Carné Trécesson, Sophie | Fétiveau, Aurélie | Sarosiek, Kristopher, A | Bock, Florian, J | Braun, Frédérique | Letai, Anthony, A | Tait, Stephen, W G | Gautier, Fabien, P | Juin, Philippe, P

Edité par CCSD ; Elsevier Inc -

International audience. 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, theactual 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 proapoptotic effectors.

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