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

eLife

Aaron M Hosios¹  John M Asara²  Margaret E Torrence³  Brendan D Manning³  Michael R MacArthur³  Alexander J Valvezan³  James R Mitchell⁴ 

[1] Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland;Center for Advanced Biotechnology and Medicine, Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, United States;Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, United States;Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, United States;

关键词: metabolism;    rapamycin;    mTOR;    integrated stress response;    xCT;    cystine;   

DOI  :  10.7554/eLife.63326

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown