Dihydroxyacetone phosphate signals glucose availability to mTORC1
Name
nihms-1606712.pdf
Description
Accepted version
Size
3.87 MB
Format
Adobe PDF
Checksum (MD5)
2be49a121760052acd6dcf55f179fe5a
Author(s)
Orozco, Jose M
Krawczyk, Patrycja A
Scaria, Sonia M
Cangelosi, Andrew L
Chan, Sze Ham
Kunchok, Tenzin
Lewis, Caroline A
Sabatini, David M
Date Issued
2020
Journal
Nature Metabolism
Publisher
Springer Science and Business Media LLC
Version
Author's final manuscript
Abstract
© 2020, The Author(s), under exclusive licence to Springer Nature Limited. 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.
MIT Department
Whitehead Institute for Biomedical Research
Massachusetts Institute of Technology. Department of Biology
Howard Hughes Medical Institute
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1038/S42255-020-0250-5
