Stabilization of ERK-Phosphorylated METTL3 by USP5 Increases m6A Methylation

Hui-Lung Sun; Allen C Zhu; Yawei Gao; Hideki Terajima; Qili Fei; Shun Liu; Linda Zhang; Zijie Zhang; Bryan T Harada; Yu-Ying He; Marc B Bissonnette; Mien-Chie Hung; Chuan He

doi:10.1016/j.molcel.2020.10.026

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.

Authors

Hui-Lung Sun¹, Allen C Zhu², Yawei Gao³, Hideki Terajima¹, Qili Fei¹, Shun Liu¹, Linda Zhang¹, Zijie Zhang¹, Bryan T Harada¹, Yu-Ying He⁴, Marc B Bissonnette⁵, Mien-Chie Hung⁶, Chuan He⁷

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: chuanhe@uchicago.edu.

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.

Published by Elsevier Inc.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adenine / analogs & derivatives*
Adenine / chemistry
Animals
Carcinogenesis / genetics
Carcinogenesis / metabolism
Carcinogenesis / pathology*
Embryo, Mammalian / cytology
Embryo, Mammalian / metabolism
Endopeptidases / genetics
Endopeptidases / metabolism*
Extracellular Signal-Regulated MAP Kinases / genetics
Extracellular Signal-Regulated MAP Kinases / metabolism*
Fibroblasts / cytology
Fibroblasts / metabolism
Humans
Melanoma / genetics
Melanoma / metabolism
Melanoma / pathology*
Methylation
Methyltransferases / chemistry*
Methyltransferases / genetics
Methyltransferases / metabolism
Methyltransferases / physiology
Mice
Mice, Knockout
Phosphorylation
Protein Stability
RNA Processing, Post-Transcriptional

Substances

Methyltransferases
Mettl3 protein, mouse
METTL3 protein, human
Extracellular Signal-Regulated MAP Kinases
Endopeptidases
ubiquitin isopeptidase
Adenine
6-methyladenine

Abstract

Publication types

MeSH terms

Substances

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