Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Isomerases / pharmacology*
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Base Sequence
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Calcineurin
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Calmodulin-Binding Proteins / antagonists & inhibitors*
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Calmodulin-Binding Proteins / physiology
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Carrier Proteins / pharmacology*
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Cyclosporine / toxicity*
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DNA Primers / chemistry
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Drug Resistance, Microbial
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Lithium / pharmacology
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Molecular Sequence Data
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Neomycin / pharmacology
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Peptidylprolyl Isomerase
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Phosphoprotein Phosphatases / antagonists & inhibitors*
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Phosphoprotein Phosphatases / physiology
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Saccharomyces cerevisiae / drug effects*
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Sodium / pharmacology
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Tacrolimus / analogs & derivatives
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Tacrolimus / toxicity*
Substances
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Calmodulin-Binding Proteins
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Carrier Proteins
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DNA Primers
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Cyclosporine
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Lithium
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Sodium
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immunomycin
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Calcineurin
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Phosphoprotein Phosphatases
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Amino Acid Isomerases
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Peptidylprolyl Isomerase
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Neomycin
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Tacrolimus