title: Tight Sequestration of BH3 Proteins by BCL-xL at Subcellular Membranes Contributes to Apoptotic Resistance.
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.
authors.affiliation: CRCNA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44035 Nantes, France.
authors.forename: Jessie
authors.initials: J
authors.lastname: Pécot
authors.affiliation: CRCNA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44035 Nantes, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Maillet
authors.affiliation: CRCNA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44035 Nantes, France.
authors.forename: Janic
authors.initials: J
authors.lastname: Le Pen
authors.affiliation: CRCNA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44035 Nantes, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Vuillier
authors.affiliation: CRCNA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44035 Nantes, France.
authors.forename: Sophie de Carné
authors.initials: SC
authors.lastname: Trécesson
authors.affiliation: CRCNA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44035 Nantes, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Fétiveau
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Kristopher A
authors.initials: KA
authors.lastname: Sarosiek
authors.affiliation: Cancer Research UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Florian J
authors.initials: FJ
authors.lastname: Bock
authors.affiliation: CRCNA, INSERM, CNRS, Université d'Angers, Université de Nantes, 44035 Nantes, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Braun
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Letai
authors.affiliation: Cancer Research UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Stephen W G
authors.initials: SWG
authors.lastname: Tait
authors.affiliation: 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.
authors.forename: Fabien
authors.initials: F
authors.lastname: Gautier
authors.affiliation: 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.
authors.forename: Philippe P
authors.initials: PP
authors.lastname: Juin
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002474:Cell-Free System; D045325:HCT116 Cells; D006801:Humans; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D010446:Peptide Fragments / Q000008:administration & dosage; D011518:Proto-Oncogene Proteins / Q000008:administration & dosage / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051020:bcl-X Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C494811:BCL2L1 protein, human; C474007:Bax protein (53-86); D000072224:Bcl-2-Like Protein 11; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein
keywords: BCL-xL; BH3 mimetic resistance; membrane localization