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

• Published in: bioRxiv
• Main Authors: Torrence, Margaret E, Macarthur, Michael R, Hosios, Aaron M, Valvezan, Alexander J, Asara, John M, Mitchell, James R, Manning, Brendan D
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 24.02.2021
• Subjects: Activating transcription factor 4; Amino acids; Glutathione; Protein biosynthesis; Rapamycin; TOR protein; tRNA
• DOI: 10.1101/2020.10.03.324186

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 adaptive stress-responsive transcription factor ATF4 through mechanisms distinct from its canonical induction by the integrated stress response (ISR). However, how ATF4 functions in response to these distinct modes of regulation and its broader role as a downstream target of mTORC1 are unknown. Therefore, we directly compared ATF4-dependent transcriptional changes induced upon activation of mTORC1 or the ISR. The mTORC1-ATF4 pathway stimulated the expression of only a subset of the ATF4 target genes stimulated 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. Competing Interest Statement Brendan Manning is a shareholder and scientific advisory board member of LAM therapeutics and Navitor Pharmaceuticals. All other authors declare no competing financial interests. Footnotes * https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE158605