2. Academic Validation
  3. Dihydroxyacetone phosphate signals glucose availability to mTORC1

Dihydroxyacetone phosphate signals glucose availability to mTORC1

  • Nat Metab. 2020 Sep;2(9):893-901. doi: 10.1038/s42255-020-0250-5.
Jose M Orozco 1 2 3 4,  Patrycja A Krawczyk 1 2 3 4,  Sonia M Scaria 1 2 3 4,  Andrew L Cangelosi 1 2 3 4,  Sze Ham Chan 1,  Tenzin Kunchok 1,  Caroline A Lewis 1,  David M Sabatini 5 6 7 8
Affiliations

Affiliations

  • 1 Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
  • 2 Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 3 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 4 Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 5 Whitehead Institute for Biomedical Research, Cambridge, MA, USA. sabatini@wi.mit.edu.
  • 6 Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, USA. sabatini@wi.mit.edu.
  • 7 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. sabatini@wi.mit.edu.
  • 8 Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. sabatini@wi.mit.edu.
PMID: 32719541 DOI: 10.1038/s42255-020-0250-5
Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) kinase regulates cell growth by setting the balance between anabolic and catabolic processes. To be active, mTORC1 requires the environmental presence of Amino acids and glucose. While a mechanistic understanding of amino acid sensing by mTORC1 is emerging, how glucose activates mTORC1 remains mysterious. Here, we used metabolically engineered human cells lacking the canonical energy sensor AMP-activated protein kinase to identify glucose-derived metabolites required to activate mTORC1 independent of energetic stress. We show that mTORC1 senses a metabolite downstream of the aldolase and upstream of the GAPDH-catalysed steps of glycolysis and pinpoint dihydroxyacetone phosphate (DHAP) as the key molecule. In cells expressing a triose kinase, the synthesis of DHAP from DHA is sufficient to activate mTORC1 even in the absence of glucose. DHAP is a precursor for lipid synthesis, a process under the control of mTORC1, which provides a potential rationale for the sensing of DHAP by mTORC1.

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