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<p>Nuclear export of messenger RNAs (mRNAs) through nuclear pore complexes (NPCs) is a critical step in gene expression. Although <i>N</i><sup>6</sup>-adenosine methylation (m<sup>6</sup>A) has been implicated in this process, the underlying mechanism remains obscure. Here we demonstrate, using single-molecule imaging, that m<sup>6</sup>A markedly accelerates the nuclear export of messenger ribonucleoproteins (mRNPs) by increasing export efficiency and shortening export time through NPCs. We further show that the m<sup>6</sup>A methyltransferase METTL3 localizes at NPCs and functionally associates with the nucleoporin NUP93 to promote the efficient export of m<sup>6</sup>A-modified mRNPs. The disruption of this functional association between METTL3 and NUP93 substantially impairs overall mRNP export efficiency. Notably, a steroid-resistant nephrotic syndrome (SRNS)-associated <i>NUP93</i> variant (c.1162C&gt;T, p.Arg388Trp) fails to associate with METTL3, resulting in the defective nuclear export of key methylated mRNAs required for kidney function. Together, our findings define an m<sup>6</sup>A–METTL3–NUP93 regulatory axis for nuclear mRNA export with broad implications for human disease.</p>

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N6-adenosine methylation enhances nuclear mRNA export through METTL3 and NUP93

  • 期刊论文

  • 发表日期：

    2026年3月5日

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  • Ji Hoon Lee,
  • Mark Tingey,
  • Zhao Zhang,
  • Florian Buerger,
  • Juyeong Hong,
  • Guanshi Zhang,
  • Mei Yang,
  • Baowen Du,
  • Ji-Hoon Jeong,
  • Kayode A. John,
  • Ian M. Tamayo,
  • Qingwei D. Zhao,
  • Friedhelm Hildebrandt,
  • Marina Đurišić,
  • Nataša Stajić,
  • Brankica Spasojević,
  • Weidong Yang,
  • Kexin Xu

摘要

Nuclear export of messenger RNAs (mRNAs) through nuclear pore complexes (NPCs) is a critical step in gene expression. Although N6-adenosine methylation (m6A) has been implicated in this process, the underlying mechanism remains obscure. Here we demonstrate, using single-molecule imaging, that m6A markedly accelerates the nuclear export of messenger ribonucleoproteins (mRNPs) by increasing export efficiency and shortening export time through NPCs. We further show that the m6A methyltransferase METTL3 localizes at NPCs and functionally associates with the nucleoporin NUP93 to promote the efficient export of m6A-modified mRNPs. The disruption of this functional association between METTL3 and NUP93 substantially impairs overall mRNP export efficiency. Notably, a steroid-resistant nephrotic syndrome (SRNS)-associated NUP93 variant (c.1162C>T, p.Arg388Trp) fails to associate with METTL3, resulting in the defective nuclear export of key methylated mRNAs required for kidney function. Together, our findings define an m6A–METTL3–NUP93 regulatory axis for nuclear mRNA export with broad implications for human disease.