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

Eunus S. Ali, Anna Lipońska, Brendan P. O'Hara, David R. Amici, Michael D. Torno, Peng Gao, John M. Asara, Mee Ngan F. Yap, Marc L. Mendillo, Issam Ben-Sahra

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish
Pages (from-to)3284-3298.e7
JournalMolecular Cell
Volume82
Issue number17
DOIs
StatePublished - Sep 1 2022

Bibliographical note

Publisher Copyright:
© 2022 Elsevier Inc.

Keywords

  • SLC4A7/NBCn1
  • bicarbonate metabolism
  • mTOR signaling
  • purine metabolism
  • pyrimidine metabolism

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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