Histatin 5 targets Trk1 potassium transporter and leads to osmotic stress response in Candida albicans
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Human salivary Histatins are a family of small histidine-rich peptides with potent antifungal activity against Candida species and other pathogenic yeasts. Their fungicidal mechanisms are initiated by binding to the cell surface Ssa1/2 proteins, followed by intracellular transport and targeting of cytoplasmic effectors that leads to cell death. In this project, we identified that the Trk1 potassium transporter provides the essential pathway for ATP loss and is the critical effector for Hst 5 toxicity in C. albicans . When we explored the functional role of Trk1p in the mechanism of other antifungal peptides we demonstrated that Trk1p mediates candidacidal activities of cysteine-free peptides, but not of defensins, and that hBD-2 and hBD-3, but not HNP-1, require Ssa1/2p for antifungal activity. Our analysis of key requirements for antifungal activity of hBD-2 and hBD-3 showed that hBD-3 has more direct effects on membrane permeability. Both hBD-2 and hBD-3 killing of C. albicans cells was energy dependent and salt-sensitive, however only hBD-2 killed in cation specific manner, indicating differences in fungicidal action among [beta]-defensins. The transcriptional response of C. albicans to Hst 5 resembled the response of cells undergoing adaptation to osmotic stress as determined by global gene expression of Hst 5 treated C. albicans cells. Activation of stress response mechanisms in C. albicans cells challenged with Hst 5 was demonstrated by the hypersensitivity of Hog1 mutant strain to Hst 5 and the activation of Hog1 MAP kinase following Hst 5 treatment. Altogether, this study provides valuable information about the role of C. albicans plasma membrane in the fungicidal action of Hst 5. Understanding of components involved in Hst 5 candidacidal action and protective mechanisms in the yeast cells provides basis for designing better therapeutic agents against oral candidiasis.