2. Academic Validation
  3. m6A modification negatively regulates translation by switching mRNA from polysome to P-body via IGF2BP3

m6A modification negatively regulates translation by switching mRNA from polysome to P-body via IGF2BP3

  • Mol Cell. 2023 Nov 24:S1097-2765(23)00911-5. doi: 10.1016/j.molcel.2023.10.040.
Ting Shan 1,  Feiyan Liu 1,  Miaomiao Wen 2,  Zonggui Chen 2,  Shaopeng Li 1,  Yafen Wang 3,  Hong Cheng 4,  Yu Zhou 5
Affiliations

Affiliations

  • 1 College of Life Sciences, TaiKang Center for Life and Medical Sciences, RNA Institute, Hubei Key Laboratory of Cell Homeostasis, Wuhan University, Wuhan, China; Frontier Science Center for Immunology and Metabolism, State Key Laboratory of Virology, Wuhan University, Wuhan, China.
  • 2 Institute of Advanced Studies, Wuhan University, Wuhan, China.
  • 3 School of Public Health, Wuhan University, Wuhan, China.
  • 4 State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
  • 5 College of Life Sciences, TaiKang Center for Life and Medical Sciences, RNA Institute, Hubei Key Laboratory of Cell Homeostasis, Wuhan University, Wuhan, China; Institute of Advanced Studies, Wuhan University, Wuhan, China; Frontier Science Center for Immunology and Metabolism, State Key Laboratory of Virology, Wuhan University, Wuhan, China. Electronic address: yu.zhou@whu.edu.cn.
PMID: 38016476 DOI: 10.1016/j.molcel.2023.10.040
Abstract

In the cytoplasm, mRNAs are dynamically partitioned into translating and non-translating pools, but the mechanism for this regulation has largely remained elusive. Here, we report that m6A regulates mRNA partitioning between polysome and P-body where a pool of non-translating mRNAs resides. By quantifying the m6A level of polysomal and cytoplasmic mRNAs with m6A-LAIC-seq and m6A-LC-MS/MS in HeLa cells, we observed that polysome-associated mRNAs are hypo-m6A-methylated, whereas those enriched in P-body are hyper-m6A-methylated. Downregulation of the m6A writer METTL14 enhances translation by switching originally hyper-m6A-modified mRNAs from P-body to polysome. Conversely, by proteomic analysis, we identify a specific m6A reader IGF2BP3 enriched in P-body, and via knockdown and molecular tethering assays, we demonstrate that IGF2BP3 is both necessary and sufficient to switch target mRNAs from polysome to P-body. These findings suggest a model for the dynamic regulation of mRNA partitioning between the translating and non-translating pools in an m6A-dependent manner.

Keywords

IGF2BP3; P-body; m(6)A modification; mRNA partitioning; polysome profiling; translation.

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