Glutaminolysis activates Rag-mTORC1 signaling

Mol Cell. 2012 Aug 10;47(3):349-58. doi: 10.1016/j.molcel.2012.05.043. Epub 2012 Jun 29.


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 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / physiology*
  • Glutamine / metabolism*
  • Guanosine Triphosphate / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Ketoglutaric Acids / metabolism*
  • Lysosomes / metabolism
  • Mice
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism*
  • Signal Transduction / physiology*
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • CRTC1 protein, human
  • Ketoglutaric Acids
  • Transcription Factors
  • Glutamine
  • Guanosine Triphosphate
  • RRAGB protein, human
  • Monomeric GTP-Binding Proteins