XPO5

Exportin-5 (XPO5) is a member of the karyopherin family of nuclear transport receptors. It mediates the Ran-GTP–dependent nuclear export of precursor microRNA (pre-miRNA) from the nucleus to the cytoplasm, a critical step in microRNA biogenesis. XPO5 recognizes the characteristic hairpin structure of pre-miRNA, which typically carries a 2-nucleotide overhang at the 3' end, and binds it in a complex with Ran-GTP.

Mechanistically, XPO5 forms a cargo–Ran-GTP complex in the nucleus and transports pre-miRNA through the nuclear pore into the cytoplasm. In the cytoplasm, Ran-GTP is hydrolyzed to Ran-GDP, leading to release of the pre-miRNA and recycling of XPO5 and Ran. Structurally, XPO5 is a large protein that contains multiple HEAT repeats, forming a curved, elongated scaffold typical of export receptors.

Functionally, the export of pre-miRNA by XPO5 is essential for the maturation of most miRNAs, which regulate gene expression post-transcriptionally by guiding RNA-induced silencing complex–mediated silencing of target mRNAs. Disruption of XPO5 function or perturbations in the Ran-GTP gradient can reduce mature miRNA levels and alter gene expression programs.

Clinical relevance, including cancer biology, reflects the importance of XPO5 in miRNA biogenesis. Altered XPO5 expression or mutations affecting its export activity have been observed in some cancers, contributing to dysregulated miRNA profiles and changes in oncogenic or tumor suppressor pathways. XPO5 remains a key component of the cellular machinery that controls RNA-based gene regulation.