Abstract
Nuclear export of messenger RNAs (mRNAs) through nuclear pore complexes (NPCs) is a critical step in gene expression. Although N(6)-adenosine methylation (m(6)A) has been implicated in this process, the underlying mechanism remains obscure. Here we demonstrate, using single-molecule imaging, that m(6)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(6)A methyltransferase METTL3 localizes at NPCs and functionally associates with the nucleoporin NUP93 to promote the efficient export of m(6)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 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 m(6)A-METTL3-NUP93 regulatory axis for nuclear mRNA export with broad implications for human disease.