title: Lysine deacetylases Hda1 and Rpd3 regulate Hsp90 function thereby governing fungal drug resistance.
abstract: 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.
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Nicole
authors.initials: N
authors.lastname: Robbins
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Leach
authors.forename: Leah E
authors.initials: LE
authors.lastname: Cowen
mesh_terms: D000107:Acetylation; D001393:Azoles / Q000494:pharmacology; D019703:Calcineurin / Q000378:metabolism; D002176:Candida albicans / Q000201:enzymology* / Q000378:metabolism; D025141:Drug Resistance, Fungal / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*
chemical_list: D001393:Azoles; D018841:HSP90 Heat-Shock Proteins; D029701:Saccharomyces cerevisiae Proteins; D019703:Calcineurin; C499673:HDA1 protein, S cerevisiae; C071665:RPD3 protein, S cerevisiae; D006655:Histone Deacetylases