Rapamycin blocks sexual development in fission yeast through inhibition ofthe cellular function of an FKBP12 homolog

FKBP12 is a ubiquitous and a highly conserved prolyl isomerase that binds t he immunosuppressive drugs FK506 and rapamycin, Members of the FKBP12 famil y have been implicated in many processes that include intracellular protein folding, transport, and assembly. In the budding yeast Saccharomyces cerev isiae and in human T cells, rapamycin forms a complex with FKBP12 that inhi bits cell cycle progression by inhibition of the TOR kinases, We reported p reviously that rapamycin does not inhibit the vegetative growth of the fiss ion yeast Schizosaccharomyces pombe; however, it specifically inhibits its sexual development. Here we show that disruption of the S, pombe FKBP12 hom olog, fkh1(+), at its chromosomal locus results in a mating-deficient pheno type that is highly similar to that obtained by treatment of wild type cell s with rapamycin, A screen for fkh1 mutants that can confer rapamycin resis tance identified five amino acids in Fkh1 that are critical for the effect of rapamycin in S, pombe, All five amino acids are located in the putative rapamycin binding pocket. Together, our findings indicate that Fkh1 has an important role in sexual development and serves as the target for rapamycin action in S. pombe.