Antifungal properties of the immunosuppressant FK-506: identification of an FK-506-responsive yeast gene distinct from FKB1.
FK-506 is a novel and potent antagonist of T-cell activation and an inhibitor of fungal growth. Its immunosuppressive activity can be antagonized by the structurally related antibiotic rapamycin, and both compounds interact with cytoplasmic FK-506-binding proteins (FKBPs) in T cells and yeast cells. In this paper, we show that FK-506 and two analogs inhibit vegetative growth of Saccharomyces cerevisiae in a fashion that parallels the immunosuppressive activity of these compounds. Yeast mutants resistant to FK-506 were isolated, and at least three complementation groups (fkr1, fkr2, and fkr3) were defined. These fkr mutants show no alteration in their levels of FK-506-binding activity. Likewise, strains carrying null alleles of FKB1 (the yeast gene coding for the FKBP) remain FK-506 sensitive, indicating that depletion of yeast FKBP is not sufficient to confer an FK-506 resistance phenotype, although fkb1 null mutants are resistant to rapamycin. FKB1 does not map to the three fkr loci defined here. These results suggest that yeast FKBP mediates the inhibitory effect of rapamycin but that at least one other protein is directly involved in mediating the activity of FK-506. Interestingly, the ability of FK-506 to rescue a temperature-sensitive growth defect of the fkr3 mutant suggests that the FKR3 gene may define such a protein.
Brizuela
L
L
Department of Infectious Disease Research, Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065.
Chrebet
G
G
Bostian
K A
KA
Parent
S A
SA
D000900:Anti-Bacterial Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000935:Antifungal Agents; D002352:Carrier Proteins / Q000235:genetics; D004352:Drug Resistance, Microbial / Q000235:genetics; D005800:Genes, Fungal / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D009154:Mutation; D011090:Polyenes / Q000494:pharmacology; D015183:Restriction Mapping; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D020123:Sirolimus; D016559:Tacrolimus; D022021:Tacrolimus Binding Proteins; D013696:Temperature
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D011090:Polyenes; D022021:Tacrolimus Binding Proteins; D020123:Sirolimus; D016559:Tacrolimus