Journal
NATURE METABOLISM
Volume 2, Issue 9, Pages 893-+Publisher
NATURE RESEARCH
DOI: 10.1038/s42255-020-0250-5
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Funding
- National Institutes of Health (NIH) [R01 CA103866, R01 CA129105, R37 AI047389]
- National Cancer Institute [F30CA210373]
- Harvard-MIT MSTP training grant from the National Institute of General Medical Sciences [T32GM007753]
- Santander Universidades mobility fund - A. Mickiewicz University in Poznan
- National Institute of Diabetes and Digestive and Kidney Diseases [F31DK113665]
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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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