title: Divergent functions of three Candida albicans zinc-cluster transcription factors (CTA4, ASG1 and CTF1) complementing pleiotropic drug resistance in Saccharomyces cerevisiae.
abstract: One of the mediators of pleiotropic drug resistance in Saccharomyces cerevisiae is the ABC-transporter gene PDR5. This gene is regulated by at least two transcription factors with Zn(2)-Cys(6) finger DNA-binding motifs, Pdr1p and Pdr3p. In this work, we searched for functional homologues of these transcription factors in Candida albicans. A C. albicans gene library was screened in a S. cerevisiae mutant lacking PDR1 and PDR3 and clones resistant to azole antifungals were isolated. From these clones, three genes responsible for azole resistance were identified. These genes (CTA4, ASG1 and CTF1) encode proteins with Zn(2)-Cys(6)-type zinc finger motifs in their N-terminal domains. The C. albicans genes expressed in S. cerevisiae could activate the transcription of a PDR5-lacZ reporter system and this reporter activity was PDRE-dependent. They could also confer resistance to azoles in a S. cerevisiae strain lacking PDR1, PDR3 and PDR5, suggesting that CTA4-, ASG1- and CTF1-dependent azole resistance can be caused by genes other than PDR5 in S. cerevisiae. Deletion of CTA4, ASG1 and CTF1 in C. albicans had no effect on fluconazole susceptibility and did not alter the expression of the ABC-transporter genes CDR1 and CDR2 or the major facilitator gene MDR1, which encode multidrug transporters known as mediators of azole resistance in C. albicans. However, additional phenotypic screening tests on the C. albicans mutants revealed that the presence of ASG1 was necessary to sustain growth on non-fermentative carbon sources (sodium acetate, acetic acid, ethanol). In conclusion, C. albicans possesses functional homologues of the S. cerevisiae Pdr1p and Pdr3p transcription factors; however, their properties in C. albicans have been rewired to other functions.
authors.affiliation: Institute of Microbiology, University of Lausanne and University Hospital Center, CH-1011 Lausanne, Switzerland.
authors.forename: Alix T
authors.initials: AT
authors.lastname: Coste
authors.affiliation: School of Biosciences, University of Exeter, Exeter EX4 4QD, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Ramsdale
authors.affiliation: Institute of Microbiology, University of Lausanne and University Hospital Center, CH-1011 Lausanne, Switzerland.
authors.forename: Françoise
authors.initials: F
authors.lastname: Ischer
authors.affiliation: Institute of Microbiology, University of Lausanne and University Hospital Center, CH-1011 Lausanne, Switzerland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Sanglard
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D019342:Acetic Acid / Q000378:metabolism; D000935:Antifungal Agents / Q000494:pharmacology; D019677:Artificial Gene Fusion; D001393:Azoles / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D002244:Carbon / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D025141:Drug Resistance, Fungal; D000431:Ethanol / Q000378:metabolism; D015725:Fluconazole / Q000494:pharmacology; D005656:Fungal Proteins / Q000096:biosynthesis / Q000235:genetics; D017353:Gene Deletion; D017930:Genes, Reporter; D005816:Genetic Complementation Test; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D019346:Sodium Acetate / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*; D016335:Zinc Fingers; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
chemical_list: D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; D001393:Azoles; C094693:CDR1 protein, Candida albicans; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; C085480:PDR1 protein, S cerevisiae; C089261:PDR3 protein, S cerevisiae; C092438:PDR5 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000431:Ethanol; D019346:Sodium Acetate; D002244:Carbon; D015725:Fluconazole; D001616:beta-Galactosidase; D015032:Zinc; D019342:Acetic Acid