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

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.

Keywords: Cell growth; MAT2A; Methionine cycle; N(6)-methyladenosine; Protein Synthesis; RNA metabolism; S-adenosylmethionine; WTAP; mTOR; mTORC1.