Cyclophilin A and Ess1 interact with and regulate silencing by the Sin3-Rpd3 histone deacetylase

• Published in: The EMBO journal 2000-07, Vol.19 (14), p.3739-3749
• Main Authors: Arévalo-Rodríguez, Miguel, Cardenas, Maria E., Wu, Xiaoyun, Hanes, Steven D., Heitman, Joseph
• Format: Article
• Language: English
• Subjects: Acetylation; cyclophilin A; cyclosporin A; DNA, Ribosomal - genetics; DNA-Binding Proteins - metabolism; Enzymatic activity; Enzyme Stability; Ess1 protein; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Fungal; Gene Silencing; Genes, Fungal - genetics; Genes, Lethal - genetics; HDAC; Histone Deacetylase Inhibitors; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Immunophilins - genetics; Immunophilins - physiology; Mitosis; Models, Biological; Mutation; NIMA-Interacting Peptidylprolyl Isomerase; parvulin; Peptidylprolyl Isomerase - genetics; Peptidylprolyl Isomerase - metabolism; Pin1; prolyl isomerases; Repressor Proteins; RNA Polymerase II - metabolism; Rpd3 protein; Saccharomyces cerevisiae; Saccharomyces cerevisiae - enzymology; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae Proteins; Sin3 protein; Suppression, Genetic; Tacrolimus Binding Proteins; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism; Yeasts
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1093/emboj/19.14.3739

Three families of prolyl isomerases have been identified: cyclophilins, FK506‐binding proteins (FKBPs) and parvulins. All 12 cyclophilins and FKBPs are dispensable for growth in yeast, whereas the one parvulin homolog, Ess1, is essential. We report here that cyclophilin A becomes essential when Ess1 function is compromised. We also show that overexpression of cyclophilin A suppresses ess1 conditional and null mutations, and that cyclophilin A enzymatic activity is required for suppression. These results indicate that cyclophilin A and Ess1 function in parallel pathways and act on common targets by a mechanism that requires prolyl isomerization. Using genetic and biochemical approaches, we found that one of these targets is the Sin3–Rpd3 histone deacetylase complex, and that cyclophilin A increases and Ess1 decreases disruption of gene silencing by this complex. We show that conditions that favor acetylation over deacetylation suppress ess1 mutations. Our findings support a model in which Ess1 and cyclophilin A modulate the activity of the Sin3–Rpd3 complex, and excess histone deacetylation causes mitotic arrest in ess1 mutants.