Candida albicans Flu1-Mediated Efflux of Salivary Histatin 5 Reduces Its Cytosolic Concentration and Fungicidal Activity

From the Department of Oral Biology University at Buffalo, Buffalo, New York 14214.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.45). 02/2013; 57(4). DOI: 10.1128/AAC.02295-12
Source: PubMed

ABSTRACT Histatin 5 is a salivary human antimicrobial peptide that is toxic to the opportunistic yeast Candida albicans. Fungicial activity of Hst 5 requires intracellular translocation and accumulation to a threshold concentration for it to disrupt cellular processes. Previously we observed that total cytosolic levels of Hst 5 were gradually reduced from intact cells, suggesting that C. albicans possesses a transport mechanism for efflux of Hst 5. Since we identified C. albicans polyamine transporters responsible for Hst 5 uptake, we hypothesized that one or more polyamine efflux transporters may be involved in the efflux of Hst 5. C. albicans FLU1 and TPO2 were found to be the closest homologs of S. cerevisiae TPO1 that encodes a major spermidine efflux transporter, indicating the products of these two genes may be involved in efflux of Hst 5. We found flu1Δ/Δ cells, but not tpo2Δ/Δ cells, had significant reduction in their rate of Hst 5 efflux, and had significantly higher cytoplasmic Hst 5 and Hst 5 susceptibility compared to wild type. We also found that flu1Δ/Δ cells had reduced biofilm formation compared to wild-type cells in the presence of Hst 5. Transcriptional levels of FLU1 were not altered over the course of treatment with Hst 5; therefore Hst 5 is not likely to induce FLU1 gene over-expression as a potential mechanism of resistance. Thus Flu1, but not Tpo2, mediates efflux of Hst 5 and is responsible for reduction of its toxicity in C. albicans.

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May 23, 2014