TitlemTORC2 Responds to Glutamine Catabolite Levels to Modulate the Hexosamine Biosynthesis Enzyme GFAT1.
Publication TypeJournal Article
Year of Publication2016
AuthorsMoloughney, JG, Kim, PK, Vega-Cotto, NM, Wu, C-C, Zhang, S, Adlam, M, Lynch, T, Chou, P-C, Rabinowitz, JD, Werlen, G, Jacinto, E
JournalMol Cell
Date Published2016 Sep 1

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.

Alternate JournalMol. Cell
PubMed ID27570073
PubMed Central IDPMC5006067
Grant ListR01 CA154674 / CA / NCI NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States
R01 GM079176 / GM / NIGMS NIH HHS / United States