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

• Published in: Molecular cell 2021-05, Vol.81 (10), p.2076-2093.e9
• Main Authors: Villa, Elodie, Sahu, Umakant, O’Hara, Brendan P., Ali, Eunus S., Helmin, Kathryn A., Asara, John M., Gao, Peng, Singer, Benjamin D., Ben-Sahra, Issam
• Format: Article
• Language: English
• Subjects: Cell growth; MAT2A; Methionine cycle; mTOR; mTORC1; N6-methyladenosine; Protein Synthesis; RNA metabolism; S-adenosylmethionine; WTAP
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2021.03.009

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. [Display omitted] •mTORC1 signaling stimulates S-adenosylmethionine synthesis•The mTORC1-c-MYC axis controls MAT2A expression•mTORC1 increases SAM levels and WTAP abundance to promote N6-methylation of mRNA•MAT2A activity is required to support protein synthesis and tumor growth Villa et al. showed that mTORC1 activation stimulates N6-adenosine methylation of mRNA (m6A) through the control of S-adenosylmethionine (SAM) synthesis and WTAP protein abundance. mTORC1 promotes an increase in WTAP levels and concordantly increases MAT2A expression for SAM production and m6A RNA methylation to support protein synthesis and tumor growth.