FK506-binding protein of Neurospora crassa (NcFKBP) mediates sensitivity to the immunosuppressant FK506; resistant mutants identify two loci

Abstract

Growth of Neurospora crassa wild-type is inhibited by micromolar concentrations of the immunosuppressive macrolide FK506. Spontaneous and induced mutations that confer resistance to FK506 identified two loci, fkr-1 and fkr-2. They map on the right arm of linkage group V on either side of inl with fkr-1 being centromere proximal. Allele fb (fkr-2) lacks immunodetectable N. crassa FK506-binding protein (NcFKBP). This demonstrates that the sensitivity of N. crassa towards FK506 is mediated by NcFKBP. FK506-binding proteins have been shown to be highly conserved, i.e., found in all eukaryotic cells tested, and to exhibit peptidyl-prolyl cis-trans isomerase (PPIase) activity in vitro. Possible functions for the loci are discussed. Apart from the resistance to FK506 no other mutant phenotype was detected not even in double mutants that lacked NcFKBP as well as cyclophilin. Cyclophilin mediates the cytotoxic effect of the immunosuppressive drug Cyclosporin A and is also characterized by PPIase activity in vitro. Both FK506-resistant alleles studied exhibit incomplete dominance in forced heterokaryons. A mechanism is proposed to explain this dominance especially in view of the NcFKBP-deficient allele, fb.