4.8 Article

The mTORC1-SLC4A7 axis stimulates bicarbonate import to enhance de novo nucleotide synthesis

Journal

MOLECULAR CELL
Volume 82, Issue 17, Pages 3284-+

Publisher

CELL PRESS
DOI: 10.1016/j.molcel.2022.06.008

Keywords

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Funding

  1. National Institutes of Health, United States [R01GM135587, R01GM143334, R01GM121359, R01AI150986, F30CA264513, T32GM008152]
  2. LAM Foundation, United States, Established Investigator Award [LAM0151E01]

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The study reveals that mTORC1 regulates the utilization of environmental bicarbonate by controlling the expression of SLC4A7, which promotes nucleotide synthesis and cell growth.
Bicarbonate (HCO3-) ions maintain pH homeostasis in eukaryotic cells and serve as a carbonyl donor to support cellular metabolism. However, whether the abundance of HCO3- is regulated or harnessed to pro-mote cell growth is unknown. The mechanistic target of rapamycin complex 1 (mTORC1) adjusts cellular metabolism to support biomass production and cell growth. We find that mTORC1 stimulates the intracellular transport of HCO3- to promote nucleotide synthesis through the selective translational regulation of the sodium bicarbonate cotransporter SLC4A7. Downstream of mTORC1, SLC4A7 mRNA translation required the S6K-dependent phosphorylation of the translation factor eIF4B. In mTORC1-driven cells, loss of SLC4A7 resulted in reduced cell and tumor growth and decreased flux through de novo purine and pyrimidine synthesis in human cells and tumors without altering the intracellular pH. Thus, mTORC1 signaling, through the control of SLC4A7 expression, harnesses environmental bicarbonate to promote anabolic metabolism, cell biomass, and growth.

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