E2F1 interacts with BCL‐xL and regulates its subcellular localization dynamics to trigger cell death

• Published in: EMBO reports Vol. 19; no. 2; pp. 234 - 243
• Main Authors: Vuillier, Céline, Lohard, Steven, Fétiveau, Aurélie, Allègre, Jennifer, Kayaci, Cémile, King, Louise E, Braun, Frédérique, Barillé‐Nion, Sophie, Gautier, Fabien, Dubrez, Laurence, Gilmore, Andrew P, Juin, Philippe P, Maillet, Laurent
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2018; Springer Nature B.V; EMBO Press; John Wiley and Sons Inc
• Subjects: Apoptosis; bcl-2 Homologous Antagonist-Killer Protein - metabolism; Bcl-x protein; bcl-X Protein - chemistry; bcl-X Protein - metabolism; BCL‐2 family; BCL‐xL mobility; Binding; Cancer; Cell Death; Cell Line, Tumor; E2F1; E2F1 Transcription Factor - chemistry; E2F1 Transcription Factor - metabolism; EMBO07; Extracellular Space - metabolism; Gene Expression Regulation - drug effects; Humans; Life Sciences; Localization; Mitochondria; Mitochondria - metabolism; Mobility; Mortality; Protein Binding; Protein Transport; Proteins; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Scientific Report; Scientific Reports; Transcription; Transcription, Genetic; Tumor suppressor genes; E2F1; BCL‐2 family; apoptosis; BCL‐xL mobility; BCL-xL mobility; BCL-2 family; E2F1 Subject Category Autophagy & Cell Death
• ISSN: 1469-221X; 1469-3178; 1469-3178
• DOI: 10.15252/embr.201744046

E2F1 is the main pro‐apoptotic effector of the pRB‐regulated tumor suppressor pathway by promoting the transcription of various pro‐apoptotic proteins. We report here that E2F1 partly localizes to mitochondria, where it favors mitochondrial outer membrane permeabilization. E2F1 interacts with BCL‐xL independently from its BH3 binding interface and induces a stabilization of BCL‐xL at mitochondrial membranes. This prevents efficient control of BCL‐xL over its binding partners, in particular over BAK resulting in the induction of cell death. We thus identify a new, non‐BH3‐binding regulator of BCL‐xL localization dynamics that influences its anti‐apoptotic activity. Synopsis E2F1 interacts with BCL‐xL, independently from its BH3 binding groove, and decreases the subcellular mobility of BCL‐xL. This interferes with its ability to inhibit mitochondrial outer membrane permeabilisation and accounts for transcription‐independent E2F1‐induced apoptosis. E2F1 exerts a non transcriptional pro‐apoptotic function at the mitochondria. E2F1 interacts with BCL‐xL. E2F1 negatively regulates BCL‐xL mobility. BCL‐xL mobility is required for efficient BAK dependent cell death inhibition. Graphical Abstract E2F1 interacts with BCL‐xL, independently from its BH3 binding groove, and decreases the subcellular mobility of BCL‐xL. This interferes with its ability to inhibit mitochondrial outer membrane permeabilisation and accounts for transcription‐independent E2F1‐induced apoptosis.