The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals

• Published in: eLife Vol. 10
• Main Authors: Torrence, Margaret E, MacArthur, Michael R, Hosios, Aaron M, Valvezan, Alexander J, Asara, John M, Mitchell, James R, Manning, Brendan D
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 01.03.2021; eLife Sciences Publications, Ltd
• Subjects: Activating transcription factor 4; Activating Transcription Factor 4 - genetics; Activating Transcription Factor 4 - metabolism; Amino acids; Animals; Cancer Biology; Cell Biology; Cell Line; Cell Line, Tumor; cystine; Embryo, Mammalian; Enzymes; Fibroblasts; Genes; Glutathione; Glutathione - biosynthesis; Growth factors; Humans; Hypoxia; Insulin; Insulin - pharmacology; integrated stress response; Kinases; Mechanistic Target of Rapamycin Complex 1 - drug effects; Mechanistic Target of Rapamycin Complex 1 - genetics; Mechanistic Target of Rapamycin Complex 1 - metabolism; Metabolism; Mice; mTOR; Phosphorylation; Protein biosynthesis; Protein synthesis; Proteins; Rapamycin; Signal Transduction; Sterols; TOR protein; Transcription factors; tRNA; Tumor cell lines; xCT; mouse; cell biology; rat; cystine; mTOR; xCT; cancer biology; metabolism; human; integrated stress response; rapamycin
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.63326

The mechanistic target of rapamycin complex 1 (mTORC1) stimulates a coordinated anabolic program in response to growth-promoting signals. Paradoxically, recent studies indicate that mTORC1 can activate the transcription factor ATF4 through mechanisms distinct from its canonical induction by the integrated stress response (ISR). However, its broader roles as a downstream target of mTORC1 are unknown. Therefore, we directly compared ATF4-dependent transcriptional changes induced upon insulin-stimulated mTORC1 signaling to those activated by the ISR. In multiple mouse embryo fibroblast and human cancer cell lines, the mTORC1-ATF4 pathway stimulated expression of only a subset of the ATF4 target genes induced by the ISR, including genes involved in amino acid uptake, synthesis, and tRNA charging. We demonstrate that ATF4 is a metabolic effector of mTORC1 involved in both its established role in promoting protein synthesis and in a previously unappreciated function for mTORC1 in stimulating cellular cystine uptake and glutathione synthesis.