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 language | English (US) |
|---|---|
| Pages (from-to) | 2076-2093.e9 |
| Journal | Molecular cell |
| Volume | 81 |
| Issue number | 10 |
| DOIs | |
| State | Published - May 20 2021 |
Funding
We would like to thank Dr. Yongchao Ma (Northwestern University) for discussions, Zhiyi Liu (LC Sciences, LLC, TX) for the m6A-seq analysis, and the Mendillo lab for the HSF1/2 antibodies. This work was supported by the Developmental Therapeutics Core at Northwestern University and the Robert H. Lurie Comprehensive Cancer Center support grant (NCI CA060553); the Northwestern proteomics core; grants from the National Institutes of Health R00CA194192-04, R01GM135587 (I.B.-S.), K08HL128867, and R01HL149883 (B.D.S.); and the LAM Foundation Career Development Award LAM0127C01-18 (I.B.-S.). E.V. is supported by the Tuberous Sclerosis Alliance postdoctoral fellowship (SP0057487) and was awarded the Philippe Foundation and Servier Institute prizes. E.V. and I.B.-S. designed the study. E.V. conducted all the experiments unless otherwise indicated. P.G. and J.M.A. performed the LC-MS analysis. U.S. and E.S.A. performed some of the cellular and molecular biological experiments. B.P.O. provided technical assistance. K.A.H. and B.D.S. performed the DNA methylation experiments. E.V. and I.B.-S. wrote the manuscript. All authors discussed the results and commented on the manuscript. The authors declare no competing interests. We would like to thank Dr. Yongchao Ma (Northwestern University) for discussions, Zhiyi Liu (LC Sciences, LLC, TX) for the m 6 A-seq analysis, and the Mendillo lab for the HSF1/2 antibodies. This work was supported by the Developmental Therapeutics Core at Northwestern University and the Robert H. Lurie Comprehensive Cancer Center support grant ( NCI CA060553 ); the Northwestern proteomics core; grants from the National Institutes of Health R00CA194192-04 , R01GM135587 (I.B.-S.), K08HL128867 , and R01HL149883 (B.D.S.); and the LAM Foundation Career Development Award LAM0127C01-18 (I.B.-S.). E.V. is supported by the Tuberous Sclerosis Alliance postdoctoral fellowship ( SP0057487 ) and was awarded the Philippe Foundation and Servier Institute prizes.
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
