mTORC2 Responds to Glutamine Catabolite Levels to Modulate the Hexosamine Biosynthesis Enzyme GFAT1. Author Joseph Moloughney, Peter Kim, Nicole Vega-Cotto, Chang-Chih Wu, Sisi Zhang, Matthew Adlam, Thomas Lynch, Po-Chien Chou, Joshua Rabinowitz, Guy Werlen, Estela Jacinto Publication Year 2016 Type Journal Article Abstract Highly proliferating cells are particularly dependent on glucose and glutamine for bioenergetics and macromolecule biosynthesis. The signals that respond to nutrient fluctuations to maintain metabolic homeostasis remain poorly understood. Here, we found that mTORC2 is activated by nutrient deprivation due to decreasing glutamine catabolites. We elucidate how mTORC2 modulates a glutamine-requiring biosynthetic pathway, the hexosamine biosynthesis pathway (HBP) via regulation of expression of glutamine:fructose-6-phosphate amidotransferase 1 (GFAT1), the rate-limiting enzyme of the HBP. GFAT1 expression is dependent on sufficient amounts of glutaminolysis catabolites particularly α-ketoglutarate, which are generated in an mTORC2-dependent manner. Additionally, mTORC2 is essential for proper expression and nuclear accumulation of the GFAT1 transcriptional regulator, Xbp1s. Thus, while mTORC1 senses amino acid abundance to promote anabolism, mTORC2 responds to declining glutamine catabolites in order to restore metabolic homeostasis. Our findings uncover the role of mTORC2 in metabolic reprogramming and have implications for understanding insulin resistance and tumorigenesis. Keywords Animals, Mice, Humans, Signal Transduction, Cell Line, Cell Proliferation, Gene Expression Regulation, HeLa Cells, Homeostasis, Multiprotein Complexes, Glucose, Cell Nucleus, Fibroblasts, TOR Serine-Threonine Kinases, Metabolomics, Mechanistic Target of Rapamycin Complex 1, Metabolome, Glutamine, Hexosamines, Ketoglutaric Acids, Mechanistic Target of Rapamycin Complex 2, Nitrogenous Group Transferases, X-Box Binding Protein 1, Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) Journal Mol Cell Volume 63 Issue 5 Pages 811-26 Date Published 2016 Sep 01 ISSN Number 1097-4164 DOI 10.1016/j.molcel.2016.07.015 Alternate Journal Mol Cell PMCID PMC5006067 PMID 27570073 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML