Disruption of the <em>UPC2</em> Gene Enhances Fluconazole Antifungal Activity by Inhibiting <em>HAC1</em> mRNA Splicing in <em>Candida albicans</em>
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Azole resistance in Candida albicans is an increasing clinical challenge. Upc2 is a key transcription factor regulating ergosterol biosynthesis, but its additional roles in azole tolerance remain unclear. This study investigated whether Upc2 contributes to azole resistance through pathways beyond ergosterol synthesis. Chemical sensitivity screening, RNA sequencing, flow cytometry, and molecular assays were performed to compare wild-type C. albicans and the upc2Δ/upc2Δ mutant under fluconazole (FLC) treatment. The UPC2 gene deletion increased intracellular calcium levels and downregulated genes in the unfolded protein response (UPR) pathway. Mechanistically, the UPC2 gene deletion impaired unconventional splicing of HAC1 mRNA, leading to accumulation of unfolded proteins and enhanced sensitivity to FLC in planktonic growth, hyphal development, and biofilm formation. Our findings reveal that Upc2 regulates proteostasis in C. albicans, and its absence enhances FLC efficacy by disrupting the UPR pathway. Targeting Upc2-mediated UPR signaling may represent a promising strategy to combat azole resistance.