Nature Communications (May 2024)
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,
- Gabriel Leprivier
Affiliations
- Tal Levy
- Department of Life Sciences, Faculty of Natural Sciences, Ben-Gurion University of the Negev
- Kai Voeltzke
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
- Laura Hruby
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
- Khawla Alasad
- Department of Life Sciences, Faculty of Natural Sciences, Ben-Gurion University of the Negev
- Zuelal Bas
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
- Marteinn Snaebjörnsson
- Biochemistry and Molecular Biology, Theodor-Boveri-Institute
- Ran Marciano
- Department of Life Sciences, Faculty of Natural Sciences, Ben-Gurion University of the Negev
- Katerina Scharov
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
- Mélanie Planque
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB
- Kim Vriens
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB
- Stefan Christen
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB
- Cornelius M. Funk
- Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK)
- Christina Hassiepen
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
- Alisa Kahler
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
- Beate Heider
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
- Daniel Picard
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
- Jonathan K. M. Lim
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
- Anja Stefanski
- Molecular Proteomics Laboratory, Biomedical Research Center (BMFZ), Heinrich Heine University, Medical Faculty
- Katja Bendrin
- Institute of Biochemistry and Molecular Biology I, Medical Faculty, Heinrich Heine University
- Andres Vargas-Toscano
- Clinic for Neurosurgery, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
- Ulf D. Kahlert
- Molecular and Experimental Surgery, University Clinic for General-, Visceral, Vascular- and Transplantation Surgery, Faculty of Medicine and University Medicine, Otto-von-Guericke-University
- Kai Stühler
- Molecular Proteomics Laboratory, Biomedical Research Center (BMFZ), Heinrich Heine University, Medical Faculty
- Marc Remke
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
- Moshe Elkabets
- The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Science, Ben-Gurion University of the Negev
- Thomas G. P. Grünewald
- Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK)
- Andreas S. Reichert
- Institute of Biochemistry and Molecular Biology I, Medical Faculty, Heinrich Heine University
- Sarah-Maria Fendt
- Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB
- Almut Schulze
- Biochemistry and Molecular Biology, Theodor-Boveri-Institute
- Guido Reifenberger
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
- Barak Rotblat
- Department of Life Sciences, Faculty of Natural Sciences, Ben-Gurion University of the Negev
- Gabriel Leprivier
- Institute of Neuropathology, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University
- DOI
- https://doi.org/10.1038/s41467-024-48386-y
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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.
