2. Academic Validation
  3. Stabilization of ERK-Phosphorylated METTL3 by USP5 Increases m6A Methylation

Stabilization of ERK-Phosphorylated METTL3 by USP5 Increases m6A Methylation

  • Mol Cell. 2020 Nov 19;80(4):633-647.e7. doi: 10.1016/j.molcel.2020.10.026.
Hui-Lung Sun 1,  Allen C Zhu 2,  Yawei Gao 3,  Hideki Terajima 1,  Qili Fei 1,  Shun Liu 1,  Linda Zhang 1,  Zijie Zhang 1,  Bryan T Harada 1,  Yu-Ying He 4,  Marc B Bissonnette 5,  Mien-Chie Hung 6,  Chuan He 7
Affiliations

Affiliations

  • 1 Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA.
  • 2 Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA; Medical Scientist Training Program, The University of Chicago, Chicago, IL 60637, USA.
  • 3 Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
  • 4 Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL 60637, USA.
  • 5 Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
  • 6 China Medical University, Taichung 404, Taiwan.
  • 7 Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA; Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA. Electronic address: [email protected].
PMID: 33217317 DOI: 10.1016/j.molcel.2020.10.026
Abstract

N6-methyladenosine (m6A) is the most abundant mRNA modification and is installed by the METTL3-METTL14-WTAP methyltransferase complex. Although the importance of m6A methylation in mRNA metabolism has been well documented recently, regulation of the m6A machinery remains obscure. Through a genome-wide CRISPR screen, we identify the ERK pathway and USP5 as positive regulators of the m6A deposition. We find that ERK phosphorylates METTL3 at S43/S50/S525 and WTAP at S306/S341, followed by deubiquitination by USP5, resulting in stabilization of the m6A methyltransferase complex. Lack of METTL3/WTAP phosphorylation reduces decay of m6A-labeled pluripotent factor transcripts and traps mouse embryonic stem cells in the pluripotent state. The same phosphorylation can also be found in ERK-activated human Cancer cells and contribute to tumorigenesis. Our study reveals an unrecognized function of ERK in regulating m6A methylation.

Keywords

ERK; METTL3 phosphorylation; USP5; m(6)A methylation; stem cell differentiation.

Figures
Products