SummaryIn Candida glabrata, the sirtuins Sir2 and Hst1 control the expression of a wide number of genes including adhesins required for host colonization and niacin transporters needed for growth. Given that these sirtuins can be inactivated during infection, we asked if their inhibition could modify the response of C. glabrata to other stressful conditions. Here, we found that deletion of HST1 decreases susceptibility of C. glabrata to fluconazole and hydrogen peroxide. The transcription factor Pdr1 and the ABC transporter Cdr1 mediated the fluconazole resistance phenotype of the hst1Δ cells, whereas the transcriptional activator Msn4 and the catalase Cta1 are necessary to provide oxidative stress resistance. We show that the transcription factor Sum1 interacts with Hst1 and participate in the regulation of these genes. Interestingly, even though C. glabrata and Saccharomyces cerevisiae are closely related phylogenetically, deletion of HST1 decreased susceptibility to fluconazole and hydrogen peroxide only in C. glabrata but not in S. cerevisiae, indicating a different transcriptional control by two similar sirtuins. Our findings suggest that Hst1 acts as a regulator of stress resistance associated-genes.

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Candida glabrata, an opportunistic fungal pathogen, adheres to mammalian epithelial cells; adherence is mediated primarily by the Epa1 adhesin. EPA1 is a member of a large gene family of $23 paralogues, which encode putative adhesins. In this study, we address how EPA1 transcription is regulated. Our data show that EPA1 expression is subject to two distinct negative regulatory mechanisms. EPA1 transcription is repressed by subtelomeric silencing: the Sir complex (Sir2-Sir4), Rap1, Rif1, yKu70, and yKu80 are required for full repression. Activation of EPA1 occurs immediately after dilution of stationary phase (SP) cells into fresh media; however, transcription is rapidly repressed again, limiting expression to lag phase, just as the cells exit stationary phase. This repression following lag phase requires a cis-acting regulatory negative element (NE) located in the EPA1 39-intergenic region and is independent of telomere proximity. Bioinformatic analysis shows that there are 10 copies of the NE-like sequence in the C. glabrata genome associated with other EPA genes as well as non-EPA genes.

Candida glabrata is a fungal pathogen frequently found as a commensal in humans. To colonize and disseminate successfully in the mammalian host, C. glabrata must detect signals within the host and reprogram gene expression to respond appropriately to hostile environmental conditions. One of the layers of regulation of expression of many virulence-related genes (adhesin-encoding genes, genes involved in response to oxidative stress and xenobiotics) is achieved through epigenetic mechanisms. Local and regional silencing is mediated by the activity of two NAD(+)-dependent histone deacetylases, Hst1 and Sir2, respectively, repressing many virulence genes. Hst1 and Sir2 interact with different repressor complexes to achieve regional or local silencing. Sir2 can associate with Sir4, which is then recruited to the telomere by Rap1 and yKu. Deacetylation of the histone tails creates high affinity binding sites for new molecules of the Sir complex, thereby spreading the silent domain over >20 kb. Many of the adhesin-encoding EPA genes are subject to this regulation. Hst1 in turn associates with the Sum1-Rfm1 complex. Sum1 is a DNA-binding protein, which recognizes specific sites at individual promoters, recruiting Hst1 to specific genes involved in the response to oxidative stress and xenobiotics, which results in their repression.

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