2. Academic Validation
  3. The mTORC1-SLC4A7 axis stimulates bicarbonate import to enhance de novo nucleotide synthesis

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

  • Mol Cell. 2022 Sep 1;82(17):3284-3298.e7. doi: 10.1016/j.molcel.2022.06.008.
Eunus S Ali 1,  Anna Lipońska 2,  Brendan P O'Hara 1,  David R Amici 1,  Michael D Torno 1,  Peng Gao 3,  John M Asara 4,  Mee-Ngan F Yap 2,  Marc L Mendillo 1,  Issam Ben-Sahra 5
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
  • 2 Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 3 Metabolomics Core Facility, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
  • 4 Mass Spectrometry Core, Beth Israel Deaconess Medical Center, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 5 Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA. Electronic address: [email protected].
PMID: 35772404 DOI: 10.1016/j.molcel.2022.06.008
Abstract

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 promote 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.

Keywords

SLC4A7/NBCn1; bicarbonate metabolism; mTOR signaling; purine metabolism; pyrimidine metabolism.

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