The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Mar 01, 2021
- Source ID
- 10.7554/elife.63326
Entities
People
- Aaron M Hosios
- Alexander J. Valvezan
- Brendan D Manning
- James R. Mitchell
- John M Asara
- Margaret E. Torrence
- Michael R Macarthur
Organizations
- ETH Zurich
- Harvard Medical School
- Harvard University
- National Institutes of Health
- Rutgers University
- United States Department of Defense