title: The Hsp90 Co-chaperones Sti1, Aha1, and P23 Regulate Adaptive Responses to Antifungal Azoles.
abstract: Heat Shock Protein 90 (Hsp90) is essential for tumor progression in humans and drug resistance in fungi. However, the roles of its many co-chaperones in antifungal resistance are unknown. In this study, by susceptibility test ofNeurospora crassamutants lacking each of 18 Hsp90/Calcineurin system member genes (including 8 Hsp90 co-chaperone genes) to antifungal drugs and other stresses, we demonstrate that the Hsp90 co-chaperones Sti1 (Hop1 in yeast), Aha1, and P23 (Sba1 in yeast) were required for the basal resistance to antifungal azoles and heat stress. Deletion of any of them resulted in hypersensitivity to azoles and heat. Liquid chromatography-mass spectrometry (LC-MS) analysis showed that the toxic sterols eburicol and 14α-methyl-3,6-diol were significantly accumulated in thesti1andp23deletion mutants after ketoconazole treatment, which has been shown before to led to cell membrane stress. At the transcriptional level, Aha1, Sti1, and P23 positively regulate responses to ketoconazole stress byerg11anderg6, key genes in the ergosterol biosynthetic pathway. Aha1, Sti1, and P23 are highly conserved in fungi, andsti1andp23deletion also increased the susceptibility to azoles inFusarium verticillioides. These results indicate that Hsp90-cochaperones Aha1, Sti1, and P23 are critical for the basal azole resistance and could be potential targets for developing new antifungal agents.
authors.affiliation: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of SciencesBeijing, China; College of Life Sciences, University of Chinese Academy of SciencesBeijing, China.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of SciencesBeijing, China; College of Life Sciences, University of Chinese Academy of SciencesBeijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xue
authors.affiliation: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of SciencesBeijing, China; College of Life Sciences, University of Chinese Academy of SciencesBeijing, China.
authors.forename: Yajing
authors.initials: Y
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences Beijing, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences Beijing, China.
authors.forename: Shaojie
authors.initials: S
authors.lastname: Li
authors.affiliation: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences Beijing, China.
authors.forename: Xianyun
authors.initials: X
authors.lastname: Sun
keywords: Hsp90; aha1; azole; co-chaperone; drug resistance; p23; sti1