TY  - JOUR
AU  - Levy, Tal
AU  - Voeltzke, Kai
AU  - Hruby, Laura
AU  - Alasad, Khawla
AU  - Bas, Zuelal
AU  - Snaebjörnsson, Marteinn Thor
AU  - Marciano, Ran
AU  - Scharov, Katerina
AU  - Planque, Mélanie
AU  - Vriens, Kim
AU  - Christen, Stefan
AU  - Funk, Cornelius
AU  - Hassiepen, Christina
AU  - Kahler, Alisa
AU  - Heider, Beate
AU  - Picard, Daniel Joseph
AU  - Lim, Jonathan K M
AU  - Stefanski, Anja
AU  - Bendrin, Katja
AU  - Vargas-Toscano, Andres
AU  - Kahlert, Ulf D
AU  - Stühler, Kai
AU  - Remke, Marc
AU  - Elkabets, Moshe
AU  - Grünewald, Thomas
AU  - Reichert, Andreas S
AU  - Fendt, Sarah-Maria
AU  - Schulze, Almut
AU  - Reifenberger, Guido
AU  - Rotblat, Barak
AU  - Leprivier, Gabriel
TI  - mTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty acid metabolism.
JO  - Nature Communications
VL  - 15
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DKFZ-2024-01032
SP  - 4083
PY  - 2024
AB  - 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.
KW  - Mechanistic Target of Rapamycin Complex 1: metabolism
KW  - Mechanistic Target of Rapamycin Complex 1: genetics
KW  - Glucose: metabolism
KW  - Acetyl-CoA Carboxylase: metabolism
KW  - Acetyl-CoA Carboxylase: genetics
KW  - Humans
KW  - Adaptor Proteins, Signal Transducing: metabolism
KW  - Adaptor Proteins, Signal Transducing: genetics
KW  - Fatty Acids: metabolism
KW  - Animals
KW  - Cell Survival
KW  - Cell Cycle Proteins: metabolism
KW  - Cell Cycle Proteins: genetics
KW  - Mice
KW  - NADP: metabolism
KW  - Protein Biosynthesis
KW  - Phosphoproteins: metabolism
KW  - Phosphoproteins: genetics
KW  - Oxidative Stress
KW  - Cell Line, Tumor
KW  - Eukaryotic Initiation Factors: metabolism
KW  - Eukaryotic Initiation Factors: genetics
LB  - PUB:(DE-HGF)16
C6  - pmid:38744825
DO  - DOI:10.1038/s41467-024-48386-y
UR  - https://inrepo02.dkfz.de/record/290199
ER  -