Calcineurin is essential in cyclosporin A- and FK506-sensitive yeast strains.
The immunophilin-immunosuppressant complexes cyclophilin-cyclosporin A (CsA) and FKBP12-FK506 inhibit the phosphatase calcineurin to block T-cell activation. Although cyclophilin A, FKBP12, and calcineurin are highly conserved from yeast to man, none had previously been shown to be essential for viability. We find that CsA-sensitive yeast strains are FK506 hypersensitive and demonstrate that calcineurin is required for viability in these strains. Mutants lacking cyclophilin A or FKBP12 are resistant to CsA or FK506, respectively. Thus, both the immunosuppressive and the antifungal actions of CsA and FK506 result from calcineurin inhibition by immunophilin-drug complexes. In yeast strains in which calcineurin is not essential, calcineurin inhibition or mutation of calcineurin confers hypersensitivity to LiCl or NaCl, suggesting that calcineurin regulates cation transport.
Breuder
T
T
Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710.
Hemenway
C S
CS
Movva
N R
NR
Cardenas
M E
ME
Heitman
J
J
D000591:Amino Acid Isomerases / Q000494:pharmacology*; D001483:Base Sequence; D019703:Calcineurin; D002148:Calmodulin-Binding Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D002352:Carrier Proteins / Q000494:pharmacology*; D016572:Cyclosporine / Q000633:toxicity*; D017931:DNA Primers / Q000737:chemistry; D004352:Drug Resistance, Microbial; D008094:Lithium / Q000494:pharmacology; D008969:Molecular Sequence Data; D009355:Neomycin / Q000494:pharmacology; D019696:Peptidylprolyl Isomerase; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000502:physiology; D012441:Saccharomyces cerevisiae / Q000187:drug effects*; D012964:Sodium / Q000494:pharmacology; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000633:toxicity*
D002148:Calmodulin-Binding Proteins; D002352:Carrier Proteins; D017931:DNA Primers; D016572:Cyclosporine; D008094:Lithium; D012964:Sodium; C058028:immunomycin; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D000591:Amino Acid Isomerases; D019696:Peptidylprolyl Isomerase; D009355:Neomycin; D016559:Tacrolimus