mTORC1 promotes cell growth via m6A-dependent mRNA degradation

Sungyun Cho, Gina Lee, Brian F. Pickering, Cholsoon Jang, Jin H. Park, Long He, Lavina Mathur, Seung Soo Kim, Sunhee Jung, Hong Wen Tang, Sebastien Monette, Joshua D. Rabinowitz, Norbert Perrimon, Samie R. Jaffrey, John Blenis

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Dysregulated mTORC1 signaling alters a wide range of cellular processes, contributing to metabolic disorders and cancer. Defining the molecular details of downstream effectors is thus critical for uncovering selective therapeutic targets. We report that mTORC1 and its downstream kinase S6K enhance eIF4A/4B-mediated translation of Wilms’ tumor 1-associated protein (WTAP), an adaptor for the N6-methyladenosine (m6A) RNA methyltransferase complex. This regulation is mediated by 5′ UTR of WTAP mRNA that is targeted by eIF4A/4B. Single-nucleotide-resolution m6A mapping revealed that MAX dimerization protein 2 (MXD2) mRNA contains m6A, and increased m6A modification enhances its degradation. WTAP induces cMyc-MAX association by suppressing MXD2 expression, which promotes cMyc transcriptional activity and proliferation of mTORC1-activated cancer cells. These results elucidate a mechanism whereby mTORC1 stimulates oncogenic signaling via m6A RNA modification and illuminates the WTAP-MXD2-cMyc axis as a potential therapeutic target for mTORC1-driven cancers.

Original languageEnglish (US)
Pages (from-to)2064-2075.e8
JournalMolecular Cell
Volume81
Issue number10
DOIs
StatePublished - May 20 2021

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Keywords

  • MXD2
  • Protein translation
  • S6K1
  • WTAP
  • YTHDF readers
  • cMyc
  • eIF4A
  • mA mRNA modification
  • mRNA stability
  • mTORC1

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