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Published June 8, 2023 | Version v1
Journal article Open

Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor

Creators

  • 1. Department of Biology, University of Fribourg, 1700 Fribourg, Switzerland
  • 2. Max Planck Institute for Biology of Ageing (MPI-AGE), 50931 Cologne, Germany
  • 3. German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
  • 4. Universidad Alfonso X el Sabio, Madrid, Spain
  • 5. Universtity of Fribourg, Switzerland

Description

Cell growth is regulated by the mammalian/mechanistic Target of Rapamycin Complex 1 (mTORC1) that functions both as a nutrient sensor and a master controller of virtually all biosynthetic pathways. This ensures that cells are metabolically active only when conditions are optimal for growth. Notably, although mTORC1 is known to regulate fatty acid (FA) biosynthesis, how and whether the cellular lipid biosynthetic capacity signals back to fine-tune mTORC1 activity remains poorly understood. Here, we show that mTORC1 senses the capacity of a cell to synthesise FAs by detecting the levels of malonyl-CoA, an intermediate of this biosynthetic pathway. We find that, in both yeast and mammalian cells, this regulation is direct, with malonyl-CoA binding to the mTOR catalytic pocket and acting as a specific ATP-competitive inhibitor. When FASN (fatty acid synthase) is downregulated/inhibited, elevated malonyl-CoA levels are channelled to proximal mTOR molecules that form direct protein-protein interactions with ACC1 (acetyl-CoA carboxylase 1) and FASN. Our findings represent a conserved, unique, homeostatic mechanism whereby impaired FA biogenesis leads to reduced mTORC1 activity to coordinately link this metabolic pathway to the overall cellular biosynthetic output. Moreover, they reveal the existence of a physiological metabolite that directly inhibits the activity of a signalling kinase in mammalian cells by competing with ATP for binding.

Notes

The deposited date contains the UPLC-MS .raw files (Thermo Fisher Orbitrap IDX) and the derived lipid peak information (injection_volume, peak height, peak area, actual RT, RT delta to expected RT, formula, adduct, m/z expected, m/z measured, m/z delta and S/N) in two .xlsx files. Further information on experimental set-up, technical details and data processing is described in the associated and above mentioned publication "Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor", published in Nature Cell Biology.

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