Proteasome homeostasis, or proteostasis, is the delicate intracellular balance between generation of newly synthesized proteins and timely degradation of damaged or misfolded proteins. This major mechanism is vital for eukaryotic cells to maintain normal cellular function and dysregulation of proteostasis can prove fatal to cells. In the opportunistic microbial pathogen Candida albicans, disruption of genes in the proteasome/ubiquitin degradation pathways are known to increase cells’ antifungal susceptibility (1). The past decade has seen an increase in persistent and recurrent infections driven by trailing growth – presence of growth by a subpopulation of cells above the theoretically-determined fungicidal dosage (2). This has prompted research to focus on intrinsic molecular mechanisms that may play an important role in determining the susceptibility of C. albicans towards antifungal treatment, particularly fluconazole. Fluconazole is the first-line therapy option for superficial and systemic fungal infections and works by inhibiting production of ergosterol, a major component of the fungal cell membrane (3). In the model yeast Saccharomyces cerevisiae, the transcription factor Rpn4 regulates the expression of proteasome subunits. We discovered that the C. albicans homolog of Rpn4 is essential for trailing growth on fluconazole, and the effect is particularly strong at human body temperature of 37ºC. Deletion of RPN4 lowers expression of genes involved in ergosterol biosynthesis, suggesting a possible mechanism by which Rpn4 might act to promote growth in the presence of fluconazole. We are currently investigating the broad effects of Rpn4 on the C. albicans transcriptome, as well as other genes involved in proteostasis to establish if there is a link between proteasome regulation and fluconazole stress.