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

Joseph G. Moloughney, Peter K. Kim, Nicole M. Vega-Cotto, Chang Chih Wu, Sisi Zhang, Matthew Adlam, Thomas Lynch, Po Chien Chou, Joshua D. Rabinowitz, Guy Werlen, Estela Jacinto

Research output: Contribution to journalArticlepeer-review

92 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)811-826
Number of pages16
JournalMolecular cell
Issue number5
StatePublished - Sep 1 2016

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology


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