Glutaminolysis activates Rag-mTORC1 signaling

Duran, R.V., Oppliger, W., Robitaille, A.M., Heiserich, L., Skendaj, R., Gottlieb, E. and Hall, M.N. (2012) Glutaminolysis activates Rag-mTORC1 signaling. Molecular Cell, 47(3), pp. 349-358. (doi: 10.1016/j.molcel.2012.05.043)

Abstract

Amino acids control cell growth via activation of the highly conserved kinase TORC1. Glutamine is a particularly important amino acid in cell growth control and metabolism. However, the role of glutamine in TORC1 activation remains poorly defined. Glutamine is metabolized through glutaminolysis to produce α-ketoglutarate. We demonstrate that glutamine in combination with leucine activates mammalian TORC1 (mTORC1) by enhancing glutaminolysis and α-ketoglutarate production. Inhibition of glutaminolysis prevented GTP loading of RagB and lysosomal translocation and subsequent activation of mTORC1. Constitutively active Rag heterodimer activated mTORC1 in the absence of glutaminolysis. Conversely, enhanced glutaminolysis or a cell-permeable α-ketoglutarate analog stimulated lysosomal translocation and activation of mTORC1. Finally, cell growth and autophagy, two processes controlled by mTORC1, were regulated by glutaminolysis. Thus, mTORC1 senses and is activated by glutamine and leucine via glutaminolysis and α-ketoglutarate production upstream of Rag. This may provide an explanation for glutamine addiction in cancer ce

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Heiserich, Ms Lisa and Duran, Dr Raul and Gottlieb, Professor Eyal
• Authors: Duran, R.V., Oppliger, W., Robitaille, A.M., Heiserich, L., Skendaj, R., Gottlieb, E., and Hall, M.N.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Molecular Cell
• ISSN: 1097-2765
• ISSN (Online): 1097-4164