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Cell Rep. 2017 Oct 31;21(5):1331-1346. doi: 10.1016/j.celrep.2017.10.029.

The mTORC1 Signaling Network Senses Changes in Cellular Purine Nucleotide Levels.

Author information

1
Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
2
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
3
Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
4
Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA. Electronic address: bmanning@hsph.harvard.edu.

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.

KEYWORDS:

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

PMID:
29091770
PMCID:
PMC5689476
DOI:
10.1016/j.celrep.2017.10.029
[Indexed for MEDLINE]
Free PMC Article

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