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

doi:10.1016/j.molcel.2021.03.009

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

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

134 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 language	English
Pages (from-to)	2076-2093.e9
Journal	Molecular Cell
Volume	81
Issue number	10
DOIs	https://doi.org/10.1016/j.molcel.2021.03.009
State	Published - May 20 2021

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Inc.

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.

Funders	Funder number
Servier Institute
National Institutes of Health (NIH)	R00CA194192-04, R01GM135587, LAM0127C01-18, R01HL149883
National Heart, Lung, and Blood Institute (NHLBI)	K08HL128867
National Childhood Cancer Registry – National Cancer Institute	CA060553
Tuberous Sclerosis Alliance	SP0057487
Northwestern Polytechnical University
Philippe Chatrier Foundation

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

Access to Document

10.1016/j.molcel.2021.03.009

Cite this

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title = "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{\textquoteright} 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-methyladenosine, Protein Synthesis, RNA metabolism, S-adenosylmethionine, WTAP, mTOR, mTORC1",

author = "Elodie Villa and Umakant Sahu and O'Hara, \{Brendan P.\} and Ali, \{Eunus S.\} and Helmin, \{Kathryn A.\} and Asara, \{John M.\} and Peng Gao and Singer, \{Benjamin D.\} and Issam Ben-Sahra",

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year = "2021",

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doi = "10.1016/j.molcel.2021.03.009",

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AU - Villa, Elodie

AU - Sahu, Umakant

AU - O'Hara, Brendan P.

AU - Ali, Eunus S.

AU - Helmin, Kathryn A.

AU - Asara, John M.

AU - Gao, Peng

AU - Singer, Benjamin D.

AU - Ben-Sahra, Issam

PY - 2021/5/20

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