Regulation of Fungal Drug Resistance and Morphogenesis by Lysine Deacetylases

Hsp90 is a molecular chaperone that governs drug resistance, morphogenesis, and virulence in the leading human fungal pathogen Candida albicans. Previous work with Saccharomyces cerevisiae and C. albicans established acetylation as a novel mechanism of post-translational control of Hsp90 in fungi and implicated lysine deacetylases (KDACs) as key regulators of resistance to the most common class of antifungals, the azoles. Here, by generating KDAC deletion mutants in azole-resistant C. albicans, we discovered high level of functional redundancy among the KDACs, and identified Hos2, Hda1, Rpd3, and Rpd31as key KDACs responsible for mediating azole resistance. Furthermore, we identified Lysine 30 and 271 as critical acetylation sites of C. albicans Hsp90, such that mutations at these residues compromised Hsp90 function. Further investigations into the circuitry through which KDACs regulates drug resistance will provide important insights into the regulatory network of C. albicans Hsp90, and suggest new targets for treating life-threatening fungal infections.