Mutations That Perturb Cyclophilin A Ligand Binding Pocket Confer Cyclosporin A Resistance in Saccharomycescerevisiae

Cárdenas, María E.; Lim, Eric; Heitman, Joseph

doi:10.1074/jbc.270.36.20997

Cited by 31 publications

(23 citation statements)

References 51 publications

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“…Studies in yeast of the effects of cyclosporine on calcineurin-dependent pathways have provided strong support for this model (22,28,29,42). Our data show a strong correlation between the maintenance of calcineurin activity and cyclosporine resistance in lymphocytes.…”

Section: Discussionsupporting

confidence: 72%

Cyclophilin A-Deficient Mice Are Resistant to Immunosuppression by Cyclosporine

Colgan

Asmal

et al. 2005

The Journal of Immunology

101

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Cyclosporine is an immunosuppressive drug that is widely used to prevent organ transplant rejection. Known intracellular ligands for cyclosporine include the cyclophilins, a large family of phylogenetically conserved proteins that potentially regulate protein folding in cells. Immunosuppression by cyclosporine is thought to result from the formation of a drug-cyclophilin complex that binds to and inhibits calcineurin, a serine/threonine phosphatase that is activated by TCR engagement. Amino acids within the cyclophilins that are critical for binding to cyclosporine have been identified. Most of these residues are highly conserved within the 15 mammalian cyclophilins, suggesting that many are potential targets for the drug. We examined the effects of cyclosporine on immune cells and mice lacking Ppia, the gene encoding the prototypical cyclophilin protein cyclophilin A. TCR-induced proliferation and signal transduction by Ppia−/− CD4+ T cells were resistant to cyclosporine, an effect that was attributable to diminished calcineurin inhibition. Immunosuppressive doses of cyclosporine failed to block the responses of Ppia−/− mice to allogeneic challenge. Rag2−/− mice reconstituted with Ppia−/− splenocytes were also cyclosporine resistant, indicating that this property is intrinsic to Ppia−/− immune cells. Thus, among multiple potential ligands, CypA is the primary mediator of immunosuppression by cyclosporine.

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Section: Discussionsupporting

confidence: 72%

Cyclophilin A-Deficient Mice Are Resistant to Immunosuppression by Cyclosporine

Colgan

Asmal

et al. 2005

The Journal of Immunology

101

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“…Proteins were transferred to nitrocellulose membranes, and Pgp was detected with the murine monoclonal anti-Pgp antibody C219 (Signet Laboratories) diluted to 1 g/ml. Cyclophilin A, FKBP12, and calcineurin B were detected with rabbit polyclonal antisera diluted 1:1000 as described previously (25,52,53). Immune complexes were detected with goat anti-mouse or goat anti-rabbit immunoglobulin coupled to horseradish peroxidase and the enhanced chemiluminescence system (Amersham Corp.).…”

Section: Methodsmentioning

confidence: 99%

Immunosuppressant Target Protein FKBP12 Is Required for P-Glycoprotein Function in Yeast

Hemenway

Heitman

1996

Journal of Biological Chemistry

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“…Proteins were resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), transferred to a polyvinylidene difluoride membrane (Immun-Blot; Bio-Rad), probed with rabbit polyclonal antiserum against Cpr1 (15), and detected by enhanced chemiluminescence (Amersham Biosciences). As controls, extracts from strains expressing wild-type Cpr1 (MAY195) or with the CPR1 gene deleted (cpr1⌬, MAY196), were analyzed.…”

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confidence: 99%

Cyclophilin A Is Localized to the Nucleus and Controls Meiosis in Saccharomyces cerevisiae

Arévalo-Rodrı́guez

Heitman²

2005

Eukaryot Cell

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Cyclophilin A is conserved from yeast to humans and mediates the ability of cyclosporine to perturb signal transduction cascades via inhibition of calcineurin. Cyclophilin A also catalyzes cis-trans peptidyl-prolyl isomerization during protein folding or conformational changes; however, cyclophilin A is not essential in yeast or human cells, and the true biological functions of this highly conserved enzyme have remained enigmatic. In Saccharomyces cerevisiae, cyclophilin A becomes essential in cells compromised for the nuclear prolyl-isomerase Ess1, and cyclophilin A physically interacts with two nuclear histone deacetylase complexes, Sin3-Rpd3 and Set3C, which both control meiosis. Here we show that cyclophilin A is localized to the nucleus in yeast cells and governs the meiotic gene program to promote efficient sporulation. The prolyl-isomerase activity of cyclophilin A is required for this meiotic function. We document that cyclophilin A physically associates with the Set3C histone deacetylase and analyze in detail the structure of this protein-protein complex. Genetic studies support a model in which cyclophilin A controls meiosis via Set3C and an additional target. Our findings reveal a novel nuclear role for cyclophilin A in governing the transcriptional program required for the vegetative to meiotic developmental switch in budding yeast.Cyclophilin A was originally identified as the intracellular receptor of the immunosuppressive drug cyclosporine (Cs), and the two molecules form a complex that binds to and inhibits the protein phosphatase calcineurin, preventing T-cell activation in mammals (36,52,53). Although cyclophilin A is highly conserved from yeast to humans, establishing the normal biological functions of this nonessential protein has proven elusive. Cyclophilin A is the founding member of a class of ubiquitous and highly conserved enzymes collectively known as peptidyl-prolyl cis-trans isomerases, or prolyl-isomerases, which catalyze cis-trans isomerization of the peptide bonds preceding proline residues. The prolyl-isomerase group spans three structurally unrelated protein families: the cyclophilins, FKBPs (for FK506 binding proteins), and parvulins (34,40,69,81). All three families are present in the budding yeast Saccharomyces cerevisiae, which expresses eight different cyclophilins (Cpr1 to Cpr8), four FKBPs (Fpr1 to Fpr4), and a single parvulin (Ess1), which is the only essential prolyl-isomerase in this organism (20,37,39). Cellular roles have been established for several prolylisomerases in both mammals and yeast. In mammals, cyclophilin A associates with the human immunodeficiency virus type 1 Gag polyprotein and is incorporated into virion particles, where it is required for human immunodeficiency virus type 1 infectivity (7,9,28,84). Cyclophilin A also binds to and regulates the tyrosine kinase Itk in T lymphocytes (11,55). FKBP12regulates the activity of the ryanodine receptor, a calcium release channel in the sarcoplasmic reticulum (61,85,86), and both FKBP12 and cyclophilin A intera...

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Mutations That Perturb Cyclophilin A Ligand Binding Pocket Confer Cyclosporin A Resistance in Saccharomycescerevisiae

Cited by 31 publications

References 51 publications

Cyclophilin A-Deficient Mice Are Resistant to Immunosuppression by Cyclosporine

Cyclophilin A-Deficient Mice Are Resistant to Immunosuppression by Cyclosporine

Immunosuppressant Target Protein FKBP12 Is Required for P-Glycoprotein Function in Yeast

Cyclophilin A Is Localized to the Nucleus and Controls Meiosis in Saccharomyces cerevisiae

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