Identification of an NTF2-related factor that binds Ran-GTP and regulates nuclear protein export

Active transport of macromolecules between the nucleus and cytoplasm requir es signals for import and export and their recognition by shuttling recepto rs. Each class of macromolecule is thought to have a distinct receptor that mediates the transport reaction. Assembly and disassembly reactions of rec eptor-substrate complexes are coordinated by Ran, a GTP-binding protein who se nucleotide state is regulated catalytically by effector proteins. Ran fu nction is modulated in a noncatalytic fashion by NTF2, a protein that media tes nuclear import of Ran-GDP. Here we characterize a novel component of th e Ran system that is 26% identical to NTF2, which based on its function we refer to as NTF2-related export protein 1 (NXT1). In contrast to NTF2, NXT1 preferentially binds Ran-GTP, and it colocalizes with the nuclear pore com plex (NPC) in mammalian cells. These properties, together with the fact tha t NXT1 shuttles between the nucleus and the cytoplasm, suggest an active ro le in nuclear transport. Indeed, NXT1 stimulates nuclear protein export of the NES-containing protein PKI in vitro. The export function of NXT1 is bla cked by the addition of leptomycin B, a compound that selectively inhibits the NES receptor Crm1. Thus, NXT1 regulates the Crm1-dependent export pathw ay through its direct interaction with Ran-GTP.