The mTORC1 Signaling Network Senses Changes in Cellular Purine Nucleotide Levels

Gerta Hoxhaj, James Hughes-Hallett, Rebecca C. Timson, Erika Ilagan, Min Yuan, John M. Asara, Issam Ben-Sahra, Brendan D. Manning

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Mechanistic (or mammalian) target of rapamycin complex 1 (mTORC1) integrates signals from growth factors and nutrients to control biosynthetic processes, including protein, lipid, and nucleic acid synthesis. We find that the mTORC1 pathway is responsive to changes in purine nucleotides in a manner analogous to its sensing of amino acids. Depletion of cellular purines, but not pyrimidines, inhibits mTORC1, and restoration of intracellular adenine nucleotides via addition of exogenous purine nucleobases or nucleosides acutely reactivates mTORC1. Adenylate sensing by mTORC1 is dependent on the tuberous sclerosis complex (TSC) protein complex and its regulation of Rheb upstream of mTORC1, but independent of energy stress and AMP-activated protein kinase (AMPK). Even though mTORC1 signaling is not acutely sensitive to changes in intracellular guanylates, long-term depletion of guanylates decreases Rheb protein levels. Our findings suggest that nucleotide sensing, like amino acid sensing, enables mTORC1 to tightly coordinate nutrient availability with the synthesis of macromolecules, such as protein and nucleic acids, produced from those nutrients. mTORC1 integrates signals from growth factors and nutrients to coordinately control macromolecular synthesis. Hoxhaj et al. identify intracellular purine nucleotides as an upstream regulatory input into the mTORC1 pathway. Acutely, mTORC1 senses adenylates in a manner dependent on the TSC complex, while prolonged guanylate depletion results in reduced Rheb levels.

Original languageEnglish (US)
Pages (from-to)1331-1346
Number of pages16
JournalCell Reports
Volume21
Issue number5
DOIs
StatePublished - Oct 31 2017
Externally publishedYes

Keywords

  • AMPK
  • ATP
  • GTP
  • Rag GTPases
  • Rheb
  • mTOR
  • nucleotides
  • nutrient sensing
  • purine
  • tuberous sclerosis complex

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Hoxhaj, G., Hughes-Hallett, J., Timson, R. C., Ilagan, E., Yuan, M., Asara, J. M., Ben-Sahra, I., & Manning, B. D. (2017). The mTORC1 Signaling Network Senses Changes in Cellular Purine Nucleotide Levels. Cell Reports, 21(5), 1331-1346. https://doi.org/10.1016/j.celrep.2017.10.029