Local silencing controls the oxidative stress response and the multidrug resistance in Candida glabrata

Area of Science:

• Microbiology
• Molecular Biology
• Biochemistry

Background:

• Sirtuins, including Hst1, regulate gene expression in *Candida glabrata*, impacting host colonization and nutrient transport.
• Sirtuin activity can be compromised during infection, prompting investigation into the effects of their inhibition on stress responses.

Purpose of the Study:

• To investigate the role of Hst1 inhibition in modifying *Candida glabrata*'s response to environmental stressors.
• To identify the molecular mechanisms underlying Hst1's influence on stress resistance.

Main Methods:

• Gene deletion studies (*hst1Δ* mutant).
• Assessment of susceptibility to fluconazole and hydrogen peroxide.
• Analysis of gene expression and protein interactions involving transcription factors (Pdr1, Msn4, Sum1) and stress-related genes (Cdr1, Cta1).

Main Results:

• Deletion of *HST1* significantly decreased susceptibility to fluconazole and hydrogen peroxide in *C. glabrata*.
• Fluconazole resistance in *hst1Δ* cells was mediated by the transcription factor Pdr1 and the ABC transporter Cdr1.
• Oxidative stress resistance involved the transcriptional activator Msn4 and the catalase Cta1, with Sum1 interacting with Hst1 in gene regulation.
• This effect was specific to *C. glabrata*, as *Saccharomyces cerevisiae* did not show similar resistance phenotypes upon *HST1* deletion.

Conclusions:

• Hst1 functions as a key regulator of stress resistance-associated genes in *Candida glabrata*.
• The transcriptional control of stress responses by Hst1 differs between *C. glabrata* and *S. cerevisiae*, despite their phylogenetic relatedness.
• Targeting Hst1 could be a potential strategy to enhance the efficacy of antifungal treatments against *C. glabrata* infections.