Candida albicans is a leading human fungal pathogen, which can cause superficial infections or life-threatening systemic disease in immunocompromised individuals. The ability to transition between yeast and filamentous forms is a major virulence trait of C. albicans, and a key regulator of this morphogenetic transition is the molecular chaperone Hsp90. To explore the mechanisms governing C. albicans morphogenesis in response to Hsp90 inhibition, we performed a functional genomic screen using the gene replacement and conditional expression (GRACE) collection to identify mutants that are defective in filamentation in response to the Hsp90 inhibitor, geldanamycin. We found that transcriptional repression of genes involved in mitochondrial function blocked filamentous growth in response to the concentration of Hsp90 inhibitor used in the screen, and this was attributable to increased resistance to the compound. Further exploration revealed that perturbation of mitochondrial function reduced susceptibility to two structurally distinct Hsp90 inhibitors, geldanamycin and radicicol, such that filamentous growth was restored in the mitochondrial mutants by increasing the compound concentration. Deletion of two representative mitochondrial genes, MSU1 and SHY1, enhanced cellular efflux and reduced susceptibility to diverse intracellularly acting compounds. Additionally, screening a C. albicans efflux pump gene deletion library implicated Yor1 in efflux of geldanamycin and Cdr1, in efflux of radicicol. Deletion of these transporter genes restored sensitivity to Hsp90 inhibitors in MSU1 and SHY1 homozygous deletion mutants, thereby enabling filamentation. Taken together, our findings suggest that mitochondrial dysregulation elevates cellular efflux and consequently reduces susceptibility to xenobiotics in C. albicans.

中文翻译：

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线粒体扰动通过改变白色念珠菌的流出来降低对异生素的敏感性。


白色念珠菌是一种主要的人类真菌病原体，可在免疫功能低下的个体中引起浅表感染或危及生命的全身性疾病。在酵母和丝状形式之间转变的能力是白色念珠菌的主要毒力特征，这种形态发生转变的关键调节因子是分子伴侣 Hsp90。为了探索控制白色念珠菌形态发生响应 Hsp90 抑制的机制，我们使用基因替换和条件表达 (GRACE) 集合进行了功能基因组筛选，以识别响应 Hsp90 抑制剂格尔德霉素而丝状化有缺陷的突变体。我们发现，参与线粒体功能的基因的转录抑制会响应筛选中使用的 Hsp90 抑制剂的浓度而阻断丝状生长，这归因于对该化合物的耐药性增加。进一步的探索表明，线粒体功能的扰动降低了对两种结构不同的 Hsp90 抑制剂（格尔德霉素和根赤霉素）的敏感性，因此通过增加化合物浓度，线粒体突变体中的丝状生长得以恢复。两个代表性线粒体基因 MSU1 和 SHY1 的缺失增强了细胞流出并降低了对多种细胞内作用化合物的敏感性。此外，筛选白色念珠菌外排泵基因缺失文库表明 Yor1 参与格尔德霉素的外流，而 Cdr1 涉及根赤霉素的外流。这些转运蛋白基因的缺失恢复了 MSU1 和 SHY1 纯合缺失突变体对 Hsp90 抑制剂的敏感性，从而实现丝状化。 综上所述，我们的研究结果表明，线粒体失调会增加细胞流出，从而降低白色念珠菌对异生素的敏感性。