The Adr1 transcription factor directs regulation of the ergosterol pathway and azole resistance in C.albicans

Abstract

AbstractTranscription factors play key roles in cellular regulation and are critical in the control of drug resistance in the fungal pathogenCandida albicans. We found that activation of the transcription factor C4_02500C_A (Adr1) conferred significant resistance against fluconazole. InSaccharomyces cerevisiae, Adr1 is a carbon-source-responsive zinc-finger transcription factor required for transcription of the glucose-repressed geneADH1and of genes required for ethanol, glycerol, and fatty acid utilization. Motif scanning of promoter elements suggests that Adr1 may be rewired in fungi and governs the ergosterol synthesis pathway inC. albicans. Because previous studies have identified the zinc-cluster transcription factor Upc2 as a regulator of the ergosterol pathway in both fungi, we examined the relationship of Adr1 and Upc2 in sterol biosynthesis inC. albicans. Phenotypic profiles of eitherADR1andUPC2modulation inC. albicansshowed differential growth in the presence of fluconazole; eitheradr1orupc2homozygous deletion results in sensitivity to the drug while their activation generates a fluconazole resistant strain. The rewiring from ergosterol synthesis to fatty acid metabolism involved all members of the Adr1 regulon except the alcohol dehydrogenase Adh1, which remains under Adr1 control in both circuits and may have been driven by the lifestyle ofS. cerevisiae, which requires the ability to both tolerate and process high concentrations of ethanol.