TAC1 , Transcriptional Activator of CDR Genes, Is a New Transcription Factor Involved in the Regulation of Candida albicans ABC Transporters CDR1 and CDR2

Coste, Alix T.; Karababa, Mahir; Ischer, Françoise; Bille, Jacques; Sanglard, Dominique

doi:10.1128/ec.3.6.1639-1652.2004

Cited by 407Antifungal resistance and susceptibilityFungal and yeast genetics researchDrug Transport and Resistance Mechanisms

TAC1 , Transcriptional Activator of CDR Genes, Is a New Transcription Factor Involved in the Regulation of Candida albicans ABC Transporters CDR1 and CDR2

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Coste, Alix T., Karababa, Mahir, Ischer, Françoise, Bille, Jacques, Sanglard, Dominique·2004·Eukaryotic Cell

DOI 10.1128/ec.3.6.1639-1652.2004PMC PMC539021

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Abstract

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.

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Triazole resistance occurs as a result of the upregulation of multidrug efflux transporters of two gene families, the ABC transporters and the major facilitator gene superfamily (MFS).
“Triazole resistance also occurs as a result of the upregulation of multidrug efflux transporters of two gene families, the ABC (ATP-binding cassette) transporters and the major facilitator gene superfamily (MFS).”
From Azole Susceptibility and Transcriptome Profiling in Candida albicans Mitochondrial Electron Transport Chain Complex I Mutants (2013) · cites this paper as [5]
Regulation of efflux protein expression can occur by gain-of-function mutations in the transcription factors Tac1p and Mrr1p that are associated with greater Cdr1p/Cdr2p or Mdr1p expression, respectively, in resistant cells.
“Regulation of efflux protein expression can also occur by gain-of-function mutations in the transcription factors Tac1p and Mrr1p that are associated with greater Cdr1p/Cdr2p or Mdr1p expression, respectively, in resistant cells (5, 6).”
From Azole Susceptibility and Transcriptome Profiling in Candida albicans Mitochondrial Electron Transport Chain Complex I Mutants (2013) · cites this paper as [5]
Deletion of snf2 in strains with TAC1GOF mutations led to only minor decreases in fluconazole MIC.
“Deletion of snf2 in strains with TAC1GOF mutations, which induce the expression of the Cdr1 and Cdr2 efflux pumps (32–34), led to only minor decreases in fluconazole MIC (Table 1).”
From Candida albicans Swi/Snf and Mediator Complexes Differentially Regulate Mrr1-Induced MDR1 Expression and Fluconazole Resistance (2017) · cites this paper as [32]
Other genes, including ERG11, CDR1, and CDR2, were largely unaffected in MRR1GOF mutant strains in the ssn3 null background.
“Other genes, including ERG11, CDR1, and CDR2, whose overexpression can lead to fluconazole resistance (2, 18, 32), were also found to be largely unaffected in MRR1GOF mutant strains in the ssn3 null background (Fig. S8).”
From Candida albicans Swi/Snf and Mediator Complexes Differentially Regulate Mrr1-Induced MDR1 Expression and Fluconazole Resistance (2017) · cites this paper as [32]
Specific mutations in the transcription factor gene TAC1 mediate expression of the genes encoding ABC transporters CDR1 and CDR2, resulting in increased azole resistance in Candida albicans.
“It has been shown that specific mutations in the transcription factor gene TAC1 mediate the expression of the genes encoding ABC transporters CDR1 and CDR2 , resulting in increased azole resistance in C. albicans (2, 3).”
From Gain-of-Function Mutations in UPC2 Are a Frequent Cause of ERG11 Upregulation in Azole-Resistant Clinical Isolates of Candida albicans (2012) · cites this paper as [3]

Nile red is a known substrate for the two major membrane transporters (ABC and MFS), which have been reported as major contributors to azole resistance in Candida.
“Nile red is a known substrate for the two major membrane transporters (ABC and MFS) which have been reported as major contributors to azole resistance in Candida51–53.”
From Repurposing approach identifies pitavastatin as a potent azole chemosensitizing agent effective against azole-resistant Candida species (2020) · cites this paper as [52]
A co-dominant mutation in the putative C-terminal activation domain confers hyperactivity of Tac1, leading to constitutive increased expression of CDR1 and CDR2.
“and that a co-dominant mutation in the putative C-terminal activation domain conferred hyperactivity of the Tac1 transcription factor, leading to constitutive increased expression of CDR1 and CDR2.80 , 81”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungusCandida albicans (2020) · cites this paper as [80]
ZCF Tac1 regulates expression of both CDR1 and CDR2.
“Importantly, the zinc cluster transcription factor (ZCF) Tac1 was discovered to regulate the expression of both CDR1 and CDR2”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungusCandida albicans (2020) · cites this paper as [80]
Presence of DREs within each gene's promoter regions contributes to induced and constitutive expression of CDR1 and CDR2, while a separate BEE contributes to CDR1 baseline expression.
“The presence of drug-responsive elements (DREs) within each gene’s respective promoter regions, for example, has been shown to contribute to the induced and constitutive expression of CDR1 and CDR2, while a separate basal expression element (BEE) contributes to CDR1 baseline expression.80 , 88 , 92”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungusCandida albicans (2020) · cites this paper as [80]
Upregulation of CDR1/CDR2 and MDR1 arises from mutations in TAC1 and MRR1 transcription factors, respectively.
“Upregulation of CDR1/CDR2 and MDR1 arises from mutations in TAC1 and MRR1 transcription factors, respectively [97, 98].”
From CandidaInfections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents (2013) · cites this paper as [97]
Transcription factors such as Tac1p and Upc2p govern the expression of many azole-responsive genes and confer azole resistance.
“In addition, transcription factors, such as Tac1p that regulates the azole efflux pumps and Upc2p that regulates ergosterol biosynthesis genes in C. albicans, govern the expression of many azole-responsive genes and confer azole resistance (Coste et al., 2004; Coste et al., 2006; Dunkel et al., 2008; Heilmann et al., 2010; Flowers et al., 2012; Vasicek et al., 2014).”
From Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles (2018) · cites this paper as Coste et al., 2004

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Authors: Coste, A. T., Karababa, M., Ischer, F., Bille, J., & Sanglard, D.
Affiliations: Centre Hospitalier Universitaire Vaudois (CH)
Institute of Microbiology, University Hospital Lausanne, Lausanne, Switzerland
Corresponding author: Sanglard, Dominique
ORCID: Coste, Alix T.
Sanglard, Dominique
Venue: Eukaryotic Cell
Publisher: American Society for Microbiology
Published: 2004-12
Volume: 3
Issue: 6
Pages: 1639-1652
ISSN: 1535-9778 (ISSN-L)
1535-9786
DOI: 10.1128/ec.3.6.1639-1652.2004
PMC: PMC539021
OpenAlex: W2107043911
Cited by: 407
References: 41
Citations by year: 2026: 12 · 2025: 19 · 2024: 17 · 2023: 22 · 2022: 19 · 2021: 28 · 2020: 22 · 2019: 25 · 2018: 15 · 2017: 23 · 2016: 17 · 2015: 17 · 2014: 25 · 2013: 17 · 2012: 13
FWCI: 7.83
Type: journal article
Language: en
Open access: diamond
doi.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Eukaryotic Cell (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
IRIS (submittedVersion)
SERVAL (Université de Lausanne) (submittedVersion)
Funders: Burroughs Wellcome Fund
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords: TAC1, Candida albicans, CDR1, CDR2, ABC transporters, transcription factors, azole resistance, fluphenazine, antifungal resistance, transcriptional regulation, HSP12
MeSH terms: Alleles, Azoles, beta-Galactosidase, Biological Transport, Candida albicans, Cell Nucleus, Cloning, Molecular, Fungal Proteins, Glutathione Transferase, Models, Genetic, Nucleic Acid Hybridization, Plasmids, Promoter Regions, Genetic, Recombinant Fusion Proteins, RNA, Messenger, Saccharomyces cerevisiae, Time Factors, Transcription Factors, Blotting, Southern, Immunoblotting, Blotting, Northern, Transcriptional Activation, Up-Regulation, Genome, Fungal, Gene Deletion, DNA Primers, ATP-Binding Cassette Transporters, Loss of Heterozygosity, Oligonucleotide Array Sequence Analysis, Membrane Transport Proteins, Green Fluorescent Proteins

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TAC1 , Transcriptional Activator of CDR Genes, Is a New Transcription Factor Involved in the Regulation of Candida albicans ABC Transporters CDR1 and CDR2

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