XPO1

XPO1, also known as exportin-1 or CRM1, is a major nuclear export receptor in eukaryotic cells. It belongs to the karyopherin family and mediates the Ran-dependent export of proteins and certain RNAs that contain a leucine-rich nuclear export signal (NES) from the nucleus to the cytoplasm.

In detail, XPO1 recognizes cargo proteins with NESs and forms a trimolecular complex with RanGTP in the nucleus. This complex is transported through the nuclear pore into the cytoplasm, where GTP hydrolysis converts RanGTP to RanGDP, triggering cargo release and recycling of XPO1. A broad range of cargoes includes tumor suppressors and cell cycle regulators such as p53, p27, and FOXO transcription factors, linking XPO1 activity to cell growth and survival. XPO1 also participates in exporting certain viral RNAs via viral proteins like HIV Rev, demonstrating its role in RNA trafficking beyond cellular proteins.

Clinical relevance arises from XPO1 overexpression observed in various cancers, where it is associated with poor prognosis. Inhibitors of XPO1, particularly selective inhibitors of nuclear export (SINE) compounds such as selinexor and verdinexor, are in clinical development or approved for certain indications. These inhibitors typically bind in the NES-binding groove of XPO1, blocking cargo export and causing nuclear retention of tumor suppressors, which can induce apoptosis in cancer cells. Selinexor (Xpovio) has approvals for multiple myeloma and certain lymphoid malignancies, with ongoing trials in other cancers.

Structurally, XPO1 is a large protein (~100 kDa) composed of HEAT repeats that form a flexible superhelix suitable for cargo recognition and transport. Its function depends on the Ran gradient and the nuclear pore complex, with directionality and recycling governed by the GTPase cycle and associated regulatory mechanisms, including post-translational modifications and interacting partners.