Role of Candida albicans Transcription Factor Upc2p in Drug Resistance and Sterol Metabolism
Open accessAbstract
In Candida albicans , drug resistance to clinically important antifungal drugs may be regulated through the action of transcription factors in a manner that may or may not be similar to regulation in Saccharomyces cerevisiae . A search of the C. albicans genome identified a single homolog of the S. cerevisiae transcription factor genes UPC2 ( ScUPC2 ) and ECM22 ( ScECM22 ) that have been associated with regulation of ergosterol biosynthesis. Sequence analysis of this C. albicans UPC2 ( CaUPC2 ) gene identifies two domains, an anchoring transmembrane domain and a transcription factor region containing multiple nuclear localization signals and a fungal Zn(2)-Cys(6) binuclear cluster domain. Heterozygous deletion, homozygous deletion, and reconstructed strains of CaUPC2 as well as the parental strain were tested against several antifungal drugs, including ergosterol biosynthesis inhibitors. The CaUPC2 homozygous deletion strain showed marked hypersusceptibility to most drugs, compared to the parental and reconstructed strains. The deletion strains accumulate significantly less radiolabeled cholesterol, suggesting reduced ergosterol scavenging in those strains. When grown under azole drug pressure, the parental, heterozygous deletion and reconstructed strains of CaUPC2 upregulate the ERG2 and ERG11 ergosterol biosynthesis genes, while the homozygous deletion strain shows no such upregulation. Consistent with these results, CaUPC2 deletion strains show reduced ergosterol levels, which may explain the increased susceptibilities of the CaUPC2 deletion strains. Thus, it appears that CaUPC2 acts as a transcription factor involved in the regulation of ergosterol biosynthetic genes and as a regulator of sterol uptake across the plasma membrane.
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Upc2p is a global transcriptional activator of the ERG genes in C. albicans and up-regulates gene expression as a compensatory mechanism in response to sterol stress.
“Similar to the situation in S. cerevisiae , Upc2p is a global transcriptional activator of the ERG genes in C. albicans and has been shown to up-regulate gene expression as a compensatory mechanism in response to sterol stress.”
From The synthesis, regulation, and functions of sterols in<i>Candida albicans</i>: Well-known but still lots to learn (2016) · cites this paper as [55]
In Candida albicans, Upc2 is a zinc-cluster transcription factor that targets genes including those of the ergosterol biosynthesis pathway.
“In Candida albicans , Upc2 is a zinc-cluster transcription factor that targets genes, including those of the ergosterol biosynthesis pathway.”
From Gain-of-Function Mutations in <i>UPC2</i> Are a Frequent Cause of <i>ERG11</i> Upregulation in Azole-Resistant Clinical Isolates of Candida albicans (2012) · cites this paper as [30]
In azole-resistant clinical isolates of C. albicans, gain-of-function mutations in UPC2 can lead to constitutive overexpression of ERG11.
“In azole-resistant clinical isolates of C. albicans, gain-of-function mutations in the zinc cluster transcription factor gene UPC2 can lead to constitutive overexpression of ERG1124.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [24]
Detailed analyses demonstrated the crucial role of Upc2A-like factors in regulation of ERG gene biosynthesis.
“Detailed analyses demonstrated the crucial role of these Upc2A-like factors in regulation of ERG gene biosynthesis [30,37,38] but little was known about the full range of their target genes.”
From The Candida glabrata Upc2A transcription factor is a global regulator of antifungal drug resistance pathways (2021) · cites this paper as [37]
Induction of ERG11 is abolished when UPC2 is deleted, and the deletion strain is hypersusceptible to azole drugs, as well as terbinafine, fenpropimorph and lovastatin, illustrating UPC2's important role in sterol biosynthesis regulation.
“However, not only was the induction of ERG11 abolished when UPC2 was deleted, but the deletion strain was also hypersusceptible to the azole drugs, as well as the squalene epoxidase (Erg1) target drug terbinafine, the Erg2 and Erg24 target drug fenpropimorph and the HMG-CoA reductase inhibitor lovastatin, illustrating UPC2’s important role in sterol biosynthesis regulation.105 , 107”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus<i>Candida albicans</i> (2020) · cites this paper as [105]
UPC2 in C. albicans up-regulates ergosterol biosynthesis genes ERG2 and ERG11 when exposed to fluconazole.
“Initially identified as a homologue of the S. cerevisiae (ScUPC2) gene, UPC2 in C. albicans was initially reported to up-regulate the ergosterol biosynthesis genes ERG2 and ERG11 when exposed to fluconazole.105”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungus<i>Candida albicans</i> (2020) · cites this paper as [105]
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References 26 · Cited by 216
- Authors
- Silver, P. M., Oliver, B. G., & White, T. C.
- Affiliations
- Center for Infectious Disease Research (US)
- Corresponding author
- White, Theodore C.
- Venue
- Eukaryotic Cell
- Publisher
- American Society for Microbiology
- Published
- 2004-12
- Volume
- 3
- Issue
- 6
- Pages
- 1391-1397
- ISSN
- 1535-9778 (ISSN-L)
- 1535-9786
- PMC
- PMC539032
- OpenAlex
- W2140936126
- Cited by
- 216
- References
- 26
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 17 · 2023: 14 · 2022: 8 · 2021: 11 · 2020: 14 · 2019: 9 · 2018: 16 · 2017: 12 · 2016: 5 · 2015: 11 · 2014: 15 · 2013: 11 · 2012: 7
- FWCI
- 2.98
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Locations
- Eukaryotic Cell (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Burroughs Wellcome Fund
- M.J. Murdock Charitable Trust
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (T32AI007509, T32-AI07509)
- National Institute of Dental and Craniofacial Research (R01DE011367, R01 DE-11367, R01 DE 14161, R01DE014161)
- 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 › Epidemiology › Fungal Infections and Studies
- Keywords
- Candida albicans, antifungal resistance, ergosterol biosynthesis, sterol metabolism, sterol uptake, azole antifungals, ERG2, ERG11, nuclear localization signal
- MeSH terms
- Candida albicans, Cell Membrane, Cholesterol, Culture Media, DNA, Ergosterol, Genotype, Heterozygote, Homozygote, Models, Genetic, Plasmids, Promoter Regions, Genetic, Saccharomyces cerevisiae, Sterols, Transcription Factors, Blotting, Southern, Blotting, Northern, Trans-Activators, Up-Regulation, Polymerase Chain Reaction, Gene Deletion, Protein Structure, Tertiary, Drug Resistance, Fungal, Saccharomyces cerevisiae Proteins
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