Candida albicans Cas5 Characterization

Candida albicans is a leading causative agent of fungal infections in humans. Resistance to current antifungal drugs arises frequently and is a major clinical problem. Development of new antifungal agents remains a difficult process, partly due to the conservation of many potential therapeutic targets between C. albicans and humans. Moreover, stress responses in C. albicans enhance antifungal tolerance and enable drug resistance. Therefore, tactical targeting of specific stress response pathways in combination with antifungal agents may provide a viable strategy to enhance the efficacy of existing antifungals and suppress the emergence of antifungal drug resistance. In a recent study, the transcription factor Cas5 was identified in a screen for genes required for tolerance to the echinocandin caspofungin, a clinically prescribed fungal cell wall synthesis inhibitor. Here, we explored the mechanism underlying Cas5-dependent caspofungin tolerance and uncovered a missing link between cell cycle progression and cell wall stress response. Specifically, we discovered that Cas5 is required for the upregulation of genes involved in cell wall remodeling and downregulation of genes involved in DNA replication in response to caspofungin-induced cell wall stress. In addition, deletion of CAS5 causes hypersensitivity to general cell wall stressors as well as uncontrolled DNA replication, implicating Cas5 as a key regulator of cell wall stress response and cell cycle progression. We further established that in response to cell wall stress, Cas5 is activated by the type I protein phosphatase Glc7 and regulates the expression of cell wall and cell cycle genes in part via physical interaction with the transcription factors Swi4 and Swi6. Together, our data supports a model in which cell wall stress results in the activation of Cas5, which negatively regulates cell cycle progression via DNA replication and allows time for the repair of the fungal cell wall. Our work illuminates a novel mechanism through which cell wall remodeling and cell cycle progression are coupled, and highlights new strategies to abrogate drug resistance of a leading human fungal pathogen.