CRM1 is responsible for intracellular transport mediated by the nuclear export signal

The discovery of nuclear export signals (NESs) in a number of proteins revealed the occurrence of signal-dependent transport of proteins from the nucleus to the cytoplasm(1-14). Although the consensus motif of the NESs has been shown to be a leucine-rich, short amino-acid sequence(2,6,7), its receptor has not been identified. A cytotoxin leptomycin B (LMB) has recently been suggested to inhibit the NES-mediated transport of Rev protein(15). Here we show that LMB is a potent and specific inhibitor of the NES-dependent nuclear export of proteins. Moreover, we have found a protein of relative molecular mass 110K (p110) in Xenopus oocyte extracts that binds to the intact NES but not to the mutated, non-functional NES. The binding of p110 to NES is inhibited by LMB. We show that p110 is CRM1, which is an evolutionarily conserved protein(16-18) originally found as an essential nuclear protein in fission yeas(16) and known as a likely target of LMB19. We also show that nuclear export of a fission yeast protein, Dsk1, which has a leucine-rich NES, is disrupted in wildtype yeast treated with LMB or in the crm1 mutant. These results indicate that CRM1 is an essential mediator of the NES-dependent nuclear export of proteins in eukaryotic cells.