Xie Jinglin L, Qin Longguang, Miao Zhengqiang, Grys Ben T, Diaz Jacinto De La Cruz, Ting Kenneth, Krieger Jonathan R, Tong Jiefei, Tan Kaeling, Leach Michelle D, Ketela Troy, Moran Michael F, Krysan Damian J, Boone Charles, Andrews Brenda J, Selmecki Anna, Ho Wong Koon, Robbins Nicole, Cowen Leah E
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada, M5G 1M1.
Faculty of Health Sciences, University of Macau, Macau SAR, 999078, China.
Nat Commun. 2017 Sep 11;8(1):499. doi: 10.1038/s41467-017-00547-y.
The capacity to coordinate environmental sensing with initiation of cellular responses underpins microbial survival and is crucial for virulence and stress responses in microbial pathogens. Here we define circuitry that enables the fungal pathogen Candida albicans to couple cell cycle dynamics with responses to cell wall stress induced by echinocandins, a front-line class of antifungal drugs. We discover that the C. albicans transcription factor Cas5 is crucial for proper cell cycle dynamics and responses to echinocandins, which inhibit β-1,3-glucan synthesis. Cas5 has distinct transcriptional targets under basal and stress conditions, is activated by the phosphatase Glc7, and can regulate the expression of target genes in concert with the transcriptional regulators Swi4 and Swi6. Thus, we illuminate a mechanism of transcriptional control that couples cell wall integrity with cell cycle regulation, and uncover circuitry governing antifungal drug resistance.Cas5 is a transcriptional regulator of responses to cell wall stress in the fungal pathogen Candida albicans. Here, Xie et al. show that Cas5 also modulates cell cycle dynamics and responses to antifungal drugs.
将环境感知与细胞反应启动相协调的能力是微生物生存的基础，对于微生物病原体的毒力和应激反应至关重要。在这里，我们定义了一种调控机制，使真菌病原体白色念珠菌能够将细胞周期动态与对棘白菌素（一类一线抗真菌药物）诱导的细胞壁应激反应联系起来。我们发现，白色念珠菌转录因子Cas5对于正常的细胞周期动态以及对抑制β-1,3-葡聚糖合成的棘白菌素的反应至关重要。Cas5在基础条件和应激条件下具有不同的转录靶点，被磷酸酶Glc7激活，并能与转录调节因子Swi4和Swi6协同调节靶基因的表达。因此，我们阐明了一种将细胞壁完整性与细胞周期调控联系起来的转录控制机制，并揭示了抗真菌药物耐药性的调控机制。Cas5是真菌病原体白色念珠菌细胞壁应激反应的转录调节因子。在这里，谢等人表明Cas5还调节细胞周期动态和对抗真菌药物的反应。
