mTORC2 Responds to Glutamine Catabolite Levels to Modulate the Hexosamine Biosynthesis Enzyme GFAT1

Mol Cell. 2016 Sep 1;63(5):811-26. doi: 10.1016/j.molcel.2016.07.015. Epub 2016 Aug 25.


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.

MeSH terms

  • Animals
  • Cell Line
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Fibroblasts / cytology
  • Fibroblasts / metabolism*
  • Gene Expression Regulation
  • Glucose / metabolism
  • Glutamine / metabolism
  • Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)
  • HeLa Cells
  • Hexosamines / biosynthesis*
  • Homeostasis
  • Humans
  • Ketoglutaric Acids / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Metabolome / genetics
  • Metabolomics
  • Mice
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Nitrogenous Group Transferases / genetics
  • Nitrogenous Group Transferases / metabolism*
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • X-Box Binding Protein 1 / genetics
  • X-Box Binding Protein 1 / metabolism*


  • Hexosamines
  • Ketoglutaric Acids
  • Multiprotein Complexes
  • X-Box Binding Protein 1
  • Xbp1 protein, mouse
  • Glutamine
  • Nitrogenous Group Transferases
  • Gfpt1 protein, mouse
  • Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • TOR Serine-Threonine Kinases
  • Glucose