Control of citrate utilization by Candida albicans Adr1

Candida albicans, a fungal commensal and pathogen, occupies diverse niches in the human host. Its broad metabolic repertoire is critical for its survival. The model yeast Saccharomyces cerevisiae provides a starting point for analysis of C. albicans physiology and regulatory circuitry, but there are many examples of rewired transcription factors that govern different processes in the two organisms. We focus here on Adr1, which in S. cerevisiae promotes alternative carbon source utilization and in C. albicans promotes ergosterol synthesis. We find that C. albicans Adr1 is also required for growth on citrate and compounds that feed into the citric acid cycle, like glutamate and malate. RNA-sequencing (RNA-seq) shows that predicted citrate metabolic genes, representing both the citric acid cycle and gluconeogenesis, are downregulated in an adr1Δ/Δ mutant. In fact, the three Adr1-dependent genes HGT17, MDH1, and PCK1 are required for growth on citrate, as indicated by deletion mutant phenotypes. The hyphal regulator EED1 has a negative role in citrate utilization, and an adr1Δ/Δ eed1Δ/Δ double mutant is defective for growth on citrate. This result argues that Adr1 acts downstream or independently of Eed1 to govern citrate utilization. C. albicans Adr1 is rewired compared to its S. cerevisiae ortholog to govern the ability to use citrate, which S. cerevisiae lacks, and potentially to respond to Eed1, for which S. cerevisiae lacks an ortholog.IMPORTANCECandida albicans is a major fungal pathogen of humans, and its ability to grow on a range of carbon sources is critical for pathogenicity. Here, we find that a known regulator of ergosterol synthesis, Adr1, is also required to use citrate as a carbon source. Adr1 acts downstream or independently of Eed1, a well-known regulator of hypha formation and citrate utilization.