mTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty acid metabolism

Tal Levy, Kai Voeltzke, Laura Hruby, Khawla Alasad, Zuelal Bas, Marteinn Snaebjörnsson, Ran Marciano, Katerina Scharov, Mélanie Planque, Kim Vriens, Stefan Christen, Cornelius M. Funk, Christina Hassiepen, Alisa Kahler, Beate Heider, Daniel Picard, Jonathan K. M. Lim, Anja Stefanski, Katja Bendrin, Andres Vargas-Toscano, Ulf D. Kahlert, Kai Stühler, Marc Remke, Moshe Elkabets, Thomas G. P. Grünewald, Andreas S. Reichert, Sarah-Maria Fendt, Almut Schulze, Guido Reifenberger, Barak Rotblat () and Gabriel Leprivier ()
Additional contact information
Tal Levy: Ben-Gurion University of the Negev
Kai Voeltzke: University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
Laura Hruby: University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
Khawla Alasad: Ben-Gurion University of the Negev
Zuelal Bas: University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
Marteinn Snaebjörnsson: Theodor-Boveri-Institute
Ran Marciano: Ben-Gurion University of the Negev
Katerina Scharov: University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
Mélanie Planque: VIB-KU Leuven Center for Cancer Biology, VIB
Kim Vriens: VIB-KU Leuven Center for Cancer Biology, VIB
Stefan Christen: VIB-KU Leuven Center for Cancer Biology, VIB
Cornelius M. Funk: German Cancer Consortium (DKTK)
Christina Hassiepen: University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
Alisa Kahler: University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
Beate Heider: University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
Daniel Picard: University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
Jonathan K. M. Lim: University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
Anja Stefanski: Heinrich Heine University, Medical Faculty
Katja Bendrin: Heinrich Heine University
Andres Vargas-Toscano: Heinrich Heine University
Ulf D. Kahlert: Otto-von-Guericke-University
Kai Stühler: Heinrich Heine University, Medical Faculty
Marc Remke: University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
Moshe Elkabets: Ben-Gurion University of the Negev
Thomas G. P. Grünewald: German Cancer Consortium (DKTK)
Andreas S. Reichert: Heinrich Heine University
Sarah-Maria Fendt: VIB-KU Leuven Center for Cancer Biology, VIB
Almut Schulze: Theodor-Boveri-Institute
Guido Reifenberger: University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
Barak Rotblat: Ben-Gurion University of the Negev
Gabriel Leprivier: University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Energetic stress compels cells to evolve adaptive mechanisms to adjust their metabolism. Inhibition of mTOR kinase complex 1 (mTORC1) is essential for cell survival during glucose starvation. How mTORC1 controls cell viability during glucose starvation is not well understood. Here we show that the mTORC1 effectors eukaryotic initiation factor 4E binding proteins 1/2 (4EBP1/2) confer protection to mammalian cells and budding yeast under glucose starvation. Mechanistically, 4EBP1/2 promote NADPH homeostasis by preventing NADPH-consuming fatty acid synthesis via translational repression of Acetyl-CoA Carboxylase 1 (ACC1), thereby mitigating oxidative stress. This has important relevance for cancer, as oncogene-transformed cells and glioma cells exploit the 4EBP1/2 regulation of ACC1 expression and redox balance to combat energetic stress, thereby supporting transformation and tumorigenicity in vitro and in vivo. Clinically, high EIF4EBP1 expression is associated with poor outcomes in several cancer types. Our data reveal that the mTORC1-4EBP1/2 axis provokes a metabolic switch essential for survival during glucose starvation which is exploited by transformed and tumor cells.

Date: 2024
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DOI: 10.1038/s41467-024-48386-y

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