The proteasome regulator Rpn4 controls antifungal drug susceptibility

In Candida albicans, the transcriptional activator Rpn4 is required for controlling the susceptibility to the frontline drug fluconazole. Our detailedanalysis has shown that C. albicans Rpn4 controls fluconazole tolerance in clinically relevant conditions, while its role in resistance is more minor. Fluconazole tolerance is different from resistance, but with poorly understood mechanisms although it enables growth of a fraction of a cell population at high drug concentrations and it could be driving therapeutic failure. Rpn4 activates proteasome gene expression; by using the proteasome inhibitor MG132 and comparing rpn4 / phenotypes at different temperatures, we provide support for Rpn4-dependent proteasome activation in fluconazole tolerance.As such, our results define a key transcriptional regulator of fluconazole tolerance and provide insight into the mechanisms by which protein and lipid homeostasis enable drug tolerance.