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

Ting Shan1, Feiyan Liu1, Miaomiao Wen2

  • 1College 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.

Molecular Cell
|November 28, 2023
PubMed

Insights

N6-methyladenosine (m6A) controls mRNA localization between translating polysomes and non-translating P-bodies. This epigenetic mark, influenced by METTL14 and IGF2BP3, dictates mRNA fate in the cytoplasm.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • RNA Biology

Background:

  • Cytoplasmic mRNA exists in translating (polysome) and non-translating (P-body) pools.
  • The regulatory mechanisms governing mRNA partitioning remain largely unknown.

Purpose of the Study:

  • To elucidate the role of N6-methyladenosine (m6A) in regulating mRNA partitioning between polysomes and P-bodies.
  • To identify key proteins involved in m6A-mediated mRNA localization.

Main Methods:

  • m6A-level quantification using m6A-LAIC-seq and m6A-LC-MS/MS in HeLa cells.
  • Knockdown and molecular tethering assays to assess protein function.
  • Proteomic analysis to identify m6A readers.

Main Results:

  • Polysome-associated mRNAs exhibit lower m6A levels, while P-body enriched mRNAs show higher m6A modification.
  • Downregulation of METTL14 promotes translation by shifting mRNAs from P-bodies to polysomes.
  • IGF2BP3 acts as an m6A reader, mediating the switch of target mRNAs from polysomes to P-bodies.

Conclusions:

  • m6A dynamically regulates mRNA partitioning between translating and non-translating cellular compartments.
  • The m6A writer METTL14 and reader IGF2BP3 are key players in this regulatory process.
  • This study proposes a model for m6A-dependent mRNA fate determination.
Keywords:
IGF2BP3P-bodym(6)A modificationmRNA partitioningpolysome profilingtranslation

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