TY - JOUR
T1 - mTORC2 Responds to Glutamine Catabolite Levels to Modulate the Hexosamine Biosynthesis Enzyme GFAT1
AU - Moloughney, Joseph G.
AU - Kim, Peter K.
AU - Vega-Cotto, Nicole M.
AU - Wu, Chang Chih
AU - Zhang, Sisi
AU - Adlam, Matthew
AU - Lynch, Thomas
AU - Chou, Po Chien
AU - Rabinowitz, Joshua D.
AU - Werlen, Guy
AU - Jacinto, Estela
N1 - Funding Information:
We thank Michael N. Hall and Markus Rüegg for providing the rictor- and raptor-flox mice and Wenyun Lu for technical assistance. This work was supported by NIH Grants GM079176 and CA154674, a Stand Up to Cancer Innovative Research Grant (Grant SU2C-AACR-IRG0311) (E.J.), a New Jersey Commission for Cancer Research Grant (J.G.M.), a Research Supplement to promote diversity in health-related research (CA-154674-04S1) (N.M.V.-C.), and NIH grant CA163591 and the SU2C Pancreatic Cancer Dream Team (J.D.R.).
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.molcel.2016.07.015
DO - 10.1016/j.molcel.2016.07.015
M3 - Article
C2 - 27570073
AN - SCOPUS:84992463377
SN - 1097-2765
VL - 63
SP - 811
EP - 826
JO - Molecular Cell
JF - Molecular Cell
IS - 5
ER -