mTORC1 stimulates cell growth through SAM synthesis and m6A mRNA-dependent control of protein synthesis

Elodie Villa, Umakant Sahu, Brendan P. O'Hara, Eunus S. Ali, Kathryn A. Helmin, John M. Asara, Peng Gao, Benjamin D. Singer, Issam Ben-Sahra*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) regulates metabolism and cell growth in response to nutrient, growth, and oncogenic signals. We found that mTORC1 stimulates the synthesis of the major methyl donor, S-adenosylmethionine (SAM), through the control of methionine adenosyltransferase 2 alpha (MAT2A) expression. The transcription factor c-MYC, downstream of mTORC1, directly binds to intron 1 of MAT2A and promotes its expression. Furthermore, mTORC1 increases the protein abundance of Wilms’ tumor 1-associating protein (WTAP), the positive regulatory subunit of the human N6-methyladenosine (m6A) RNA methyltransferase complex. Through the control of MAT2A and WTAP levels, mTORC1 signaling stimulates m6A RNA modification to promote protein synthesis and cell growth. A decline in intracellular SAM levels upon MAT2A inhibition decreases m6A RNA modification, protein synthesis rate, and tumor growth. Thus, mTORC1 adjusts m6A RNA modification through the control of SAM and WTAP levels to prime the translation machinery for anabolic cell growth.

Original languageEnglish (US)
Pages (from-to)2076-2093.e9
JournalMolecular cell
Volume81
Issue number10
DOIs
StatePublished - May 20 2021

Keywords

  • Cell growth
  • MAT2A
  • Methionine cycle
  • N-methyladenosine
  • Protein Synthesis
  • RNA metabolism
  • S-adenosylmethionine
  • WTAP
  • mTOR
  • mTORC1

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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