The molecular chaperone Hsp90 is a hub of protein homeostasis and regulatory circuitry. Hsp90 function is regulated by posttranslational modifications including acetylation in mammals; however, whether this regulation is conserved remains unknown. In fungi, Hsp90 governs the evolution of drug resistance by stabilizing signal transducers. Here, we establish that pharmacological inhibition of lysine deacetylases (KDACs) blocks the emergence and maintenance of Hsp90-dependent resistance to the most widely deployed antifungals, the azoles, in the human fungal pathogen Candida albicans and the model yeast Saccharomyces cerevisiae. S. cerevisiae Hsp90 is acetylated on lysine 27 and 270, and key KDACs for drug resistance are Hda1 and Rpd3. Compromising KDACs alters stability and function of Hsp90 client proteins, including the drug-resistance regulator calcineurin. Thus, we establish acetylation as a mechanism of posttranslational control of Hsp90 function in fungi, functional redundancy between KDACs Hda1 and Rpd3, as well as a mechanism governing fungal drug resistance with broad therapeutic potential.
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| Evidence ID | Analyze ID | Gene/Complex | Systematic Name/Complex Accession | Qualifier | Gene Ontology Term ID | Gene Ontology Term | Aspect | Annotation Extension | Evidence | Method | Source | Assigned On | Reference |
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| Evidence ID | Analyze ID | Gene | Gene Systematic Name | Phenotype | Experiment Type | Experiment Type Category | Mutant Information | Strain Background | Chemical | Details | Reference |
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| Evidence ID | Analyze ID | Gene | Gene Systematic Name | Disease Ontology Term | Disease Ontology Term ID | Qualifier | Evidence | Method | Source | Assigned On | Reference |
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| Evidence ID | Analyze ID | Regulator | Regulator Systematic Name | Target | Target Systematic Name | Direction | Regulation of | Happens During | Regulator Type | Direction | Regulation Of | Happens During | Method | Evidence | Strain Background | Reference |
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| Site | Modification | Modifier | Source | Reference |
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| Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Allele | Assay | Annotation | Action | Phenotype | SGA score | P-value | Source | Reference | Note |
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| Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Assay | Annotation | Action | Modification | Source | Reference | Note |
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| Complement ID | Locus ID | Gene | Species | Gene ID | Strain background | Direction | Details | Source | Reference |
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| Evidence ID | Analyze ID | Dataset | Description | Keywords | Number of Conditions | Reference |
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| Evidence ID | Analyze ID | File | Description |
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