| Title: |
mTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty acid metabolism |
| Authors: |
Levy, Tal; Voeltzke, Kai; Hruby, Laura; Alasad, Khawla; Bas, Zuelal; Snaebjoernsson, Marteinn; Marciano, Ran; Scharov, Katerina; Planque, Melanie; Vriens, Kim; Christen, Stefan; Funk, Cornelius M.; Hassiepen, Christina; Kahler, Alisa; Heider, Beate; Picard, Daniel; Lim, Jonathan K.M.; Stefanski, Anja; Bendrin, Katja; Vargas-Toscano, Andres; Kahlert, Ulf D.; Stuehler, Kai; Remke, Marc; Elkabets, Moshe; Gruenewald, Thomas G.P.; Reichert, Andreas S.; Fendt, Sarah-Maria; Schulze, Almut; Reifenberger, Guido; Rotblat, Barak; Leprivier, Gabriel |
| Source: |
ISSN:2041-1723 ; Nature Communications, vol. 15 (1), Art.No. ARTN 4083. |
| Publisher Information: |
Nature Portfolio |
| Publication Year: |
2024 |
| Subject Terms: |
Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; MESSENGER-RNA; INITIATION; CANCER; PROTEIN; HOMEOSTASIS; GROWTH; EIF4E; PHOSPHORYLATION; DEPRIVATION; INHIBITOR; Animals; Humans; Mice; Acetyl-CoA Carboxylase; Adaptor Proteins; Signal Transducing; Cell Cycle Proteins; Cell Line; Tumor; Cell Survival; Eukaryotic Initiation Factors; Fatty Acids; Glucose; Mechanistic Target of Rapamycin Complex 1; NADP; Oxidative Stress; Phosphoproteins |
| Description: |
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. ; sponsorship: We would like to thank Maya Bar and Bjoern Stork for helpful discussions. We would like to thank Marc B. Hershenson (University of Michigan) for providing us the MSCV puro-4EBP1 (T37A/T46A) plasmid. This work was supported by funds from the Israel Cancer Association (grant no. 20220143), the ISRAEL SCIENCE FOUNDATION (grant no. 1436/19) and the NIBN to B.R.; the Dr. Rolf M. Schwiete Stiftung (grant no. 2020-018) to L.H. and G.L.; the Deutsche Forschungsgemeinschaft (grant no. LE 3751/2-1), the German Cancer Aid (grants no. 70112624 and 70115129), the Elterninitiative Duesseldorf e.V. (grant no. 701910003), and the Research Commission of the Medical Faculty, Heinrich Heine University Duesseldorf (grants no. 2016-056 and 2020-044) to G.L.; the Matthias-Lackas foundation, the Dr. Leopold und Carmen Ellinger foundation, the European ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://lirias.kuleuven.be/handle/20.500.12942/742230; https://pubmed.ncbi.nlm.nih.gov/38744825 |
| DOI: |
10.1038/s41467-024-48386-y |
| Availability: |
https://lirias.kuleuven.be/handle/20.500.12942/742230; https://hdl.handle.net/20.500.12942/742230; https://lirias.kuleuven.be/retrieve/0e34c557-0d74-47dd-9601-3a2bdc92dc0c; https://doi.org/10.1038/s41467-024-48386-y; https://pubmed.ncbi.nlm.nih.gov/38744825 |
| Rights: |
info:eu-repo/semantics/openAccess ; public ; https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.684103C2 |
| Database: |
BASE |