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

doi:10.1016/j.molcel.2022.06.008

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

20 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 language	English (US)
Pages (from-to)	3284-3298.e7
Journal	Molecular cell
Volume	82
Issue number	17
DOIs	https://doi.org/10.1016/j.molcel.2022.06.008
State	Published - Sep 1 2022

Funding

This work was supported by grants from the National Institutes of Health, United States, R01GM135587, R01GM143334 (I.B.-S.), R01GM121359, R01AI150986 (M.-N.F.Y.), F30CA264513, and T32GM008152 (D.R.A.); and by the LAM Foundation, United States, Established Investigator Award LAM0151E01-22 (I.B.-S.). E.S.A. performed and analyzed all experiments and prepared the manuscript. P.G. and J.M.A. performed the LC-MS analysis. B.P.O. and M.D.T. provided technical assistance. A.L. and M.-N.F.Y. provided technical expertise on the polysome profiling assay. D.R.A. and M.L.M. performed the coessentiality analysis. I.B.-S. supervised the project, reviewed all experimental data, and prepared the manuscript. All authors discussed the results and commented on the manuscript. The authors declare no conflict of interests. This work was supported by grants from the National Institutes of Health , United States, R01GM135587 , R01GM143334 (I.B.-S.), R01GM121359 , R01AI150986 (M.-N.F.Y.), F30CA264513 , and T32GM008152 (D.R.A.); and by the LAM Foundation, United States, Established Investigator Award LAM0151E01-22 (I.B.-S.).

Keywords

SLC4A7/NBCn1
bicarbonate metabolism
mTOR signaling
purine metabolism
pyrimidine metabolism

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2022.06.008

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title = "The mTORC1-SLC4A7 axis stimulates bicarbonate import to enhance de novo nucleotide synthesis",

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.",

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AU - Ali, Eunus S.

AU - Lipońska, Anna

AU - O'Hara, Brendan P.

AU - Amici, David R.

AU - Torno, Michael D.

AU - Gao, Peng

AU - Asara, John M.

AU - Yap, Mee Ngan F.

AU - Mendillo, Marc L.

AU - Ben-Sahra, Issam

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AB - 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.

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KW - pyrimidine metabolism

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

Abstract

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Keywords

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