TAC1, transcriptional activator of CDR genes, is a new transcription factor involved in the regulation of Candida albicans ABC transporters CDR1 and CDR2.
The ABC transporter genes CDR1 and CDR2 can be upregulated in Candida albicans developing resistance to azoles or can be upregulated by exposing cells transiently to drugs such as fluphenazine. The cis-acting drug-responsive element (DRE) present in the promoters of both genes and necessary for their upregulation contains 5'-CGG-3' triplets that are often recognized by transcriptional activators with Zn(2)-Cys(6) fingers. In order to isolate regulators of CDR1 and CDR2, the C. albicans genome was searched for genes encoding proteins with Zn(2)-Cys(6) fingers. Interestingly, three of these genes were tandemly arranged near the mating locus. Their involvement in CDR1 and CDR2 upregulation was addressed because a previous study demonstrated a link between mating locus homozygosity and azole resistance. The deletion of only one of these genes (orf19.3188) was sufficient to result in a loss of transient CDR1 and CDR2 upregulation by fluphenazine and was therefore named TAC1 (transcriptional activator of CDR genes). Tac1p has a nuclear localization, and a fusion of Tac1p with glutathione S-transferase could bind the cis-acting regulatory DRE in both the CDR1 and the CDR2 promoters. TAC1 is also relevant for azole resistance, since a TAC1 allele (TAC1-2) recovered from an azole-resistant strain could trigger constitutive upregulation of CDR1 and CDR2 in an azole-susceptible laboratory strain. Transcript profiling experiments performed with a TAC1 mutant and a revertant containing TAC1-2 revealed not only CDR1 and CDR2 as targets of TAC1 regulation but also other genes (RTA3, IFU5, and HSP12) that interestingly contained a DRE-like element in their promoters. In conclusion, TAC1 appears to be the first C. albicans transcription factor involved in the control of genes mediating antifungal resistance.
Coste
Alix T
AT
Institute of Microbiology, University Hospital Lausanne, Rue du Bugnon 48, CH-1011 Lausanne, Switzerland.
Karababa
Mahir
M
Ischer
Françoise
F
Bille
Jacques
J
Sanglard
Dominique
D
D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000483:Alleles; D001393:Azoles / Q000378:metabolism; D001692:Biological Transport; D015152:Blotting, Northern; D015139:Blotting, Southern; D002176:Candida albicans / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D003001:Cloning, Molecular; D017931:DNA Primers / Q000737:chemistry; D005656:Fungal Proteins / Q000502:physiology*; D017353:Gene Deletion; D016681:Genome, Fungal; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D015151:Immunoblotting; D019656:Loss of Heterozygosity; D026901:Membrane Transport Proteins / Q000502:physiology*; D008957:Models, Genetic; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation; D001616:beta-Galactosidase / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D001393:Azoles; C094693:CDR1 protein, Candida albicans; D017931:DNA Primers; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D005982:Glutathione Transferase; D001616:beta-Galactosidase