CRM1 mediates the nuclear export of YTHDF2.

Precise intracellular localization is crucial for protein function. YTHDF2, a reader protein for N6-methyladenosine (mA), has been reported to shuttle between the cytoplasm and nucleus through an unknown mechanism. Here, we identify a functional nuclear export sequence (NES) in YTHDF2 that mediates its nuclear export. Mutation of the NES leads to nuclear accumulation of YTHDF2. Wild-type YTHDF2, but not the NES-mutant, interacts with the nuclear export receptor CRM1. Inhibition of CRM1 using the specific inhibitor leptomycin B or CRM1 knockdown effectively blocks YTHDF2 nuclear export. Using a tethering reporter system, we demonstrate that NES mutation impairs the mRNA degradation activity of YTHDF2. These findings provide mechanistic insights into the regulation of YTHDF2 subcellular localization and may have therapeutic implications for YTHDF2-associated diseases.