The Candida glabrata Upc2A transcription factor is a global regulator of antifungal drug resistance pathways.
The most commonly used antifungal drugs are the azole compounds, which interfere with biosynthesis of the fungal-specific sterol: ergosterol. The pathogenic yeast Candida glabrata commonly acquires resistance to azole drugs like fluconazole via mutations in a gene encoding a transcription factor cal...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2021-09-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1009582 |
| _version_ | 1798033552274620416 |
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| author | Bao Gia Vu Mark A Stamnes Yu Li P David Rogers W Scott Moye-Rowley |
| author_facet | Bao Gia Vu Mark A Stamnes Yu Li P David Rogers W Scott Moye-Rowley |
| author_sort | Bao Gia Vu |
| collection | DOAJ |
| description | The most commonly used antifungal drugs are the azole compounds, which interfere with biosynthesis of the fungal-specific sterol: ergosterol. The pathogenic yeast Candida glabrata commonly acquires resistance to azole drugs like fluconazole via mutations in a gene encoding a transcription factor called PDR1. These PDR1 mutations lead to overproduction of drug transporter proteins like the ATP-binding cassette transporter Cdr1. In other Candida species, mutant forms of a transcription factor called Upc2 are associated with azole resistance, owing to the important role of this protein in control of expression of genes encoding enzymes involved in the ergosterol biosynthetic pathway. Recently, the C. glabrata Upc2A factor was demonstrated to be required for normal azole resistance, even in the presence of a hyperactive mutant form of PDR1. Using genome-scale approaches, we define the network of genes bound and regulated by Upc2A. By analogy to a previously described hyperactive UPC2 mutation found in Saccharomyces cerevisiae, we generated a similar form of Upc2A in C. glabrata called G898D Upc2A. Analysis of Upc2A genomic binding sites demonstrated that wild-type Upc2A binding to target genes was strongly induced by fluconazole while G898D Upc2A bound similarly, irrespective of drug treatment. Transcriptomic analyses revealed that, in addition to the well-described ERG genes, a large group of genes encoding components of the translational apparatus along with membrane proteins were responsive to Upc2A. These Upc2A-regulated membrane protein-encoding genes are often targets of the Pdr1 transcription factor, demonstrating the high degree of overlap between these two regulatory networks. Finally, we provide evidence that Upc2A impacts the Pdr1-Cdr1 system and also modulates resistance to caspofungin. These studies provide a new perspective of Upc2A as a master regulator of lipid and membrane protein biosynthesis. |
| first_indexed | 2024-04-11T20:32:15Z |
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| id | doaj.art-2e15523381bb4fc399fa53d9a69a1cda |
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| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-11T20:32:15Z |
| publishDate | 2021-09-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Genetics |
| spelling | doaj.art-2e15523381bb4fc399fa53d9a69a1cda2022-12-22T04:04:28ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042021-09-01179e100958210.1371/journal.pgen.1009582The Candida glabrata Upc2A transcription factor is a global regulator of antifungal drug resistance pathways.Bao Gia VuMark A StamnesYu LiP David RogersW Scott Moye-RowleyThe most commonly used antifungal drugs are the azole compounds, which interfere with biosynthesis of the fungal-specific sterol: ergosterol. The pathogenic yeast Candida glabrata commonly acquires resistance to azole drugs like fluconazole via mutations in a gene encoding a transcription factor called PDR1. These PDR1 mutations lead to overproduction of drug transporter proteins like the ATP-binding cassette transporter Cdr1. In other Candida species, mutant forms of a transcription factor called Upc2 are associated with azole resistance, owing to the important role of this protein in control of expression of genes encoding enzymes involved in the ergosterol biosynthetic pathway. Recently, the C. glabrata Upc2A factor was demonstrated to be required for normal azole resistance, even in the presence of a hyperactive mutant form of PDR1. Using genome-scale approaches, we define the network of genes bound and regulated by Upc2A. By analogy to a previously described hyperactive UPC2 mutation found in Saccharomyces cerevisiae, we generated a similar form of Upc2A in C. glabrata called G898D Upc2A. Analysis of Upc2A genomic binding sites demonstrated that wild-type Upc2A binding to target genes was strongly induced by fluconazole while G898D Upc2A bound similarly, irrespective of drug treatment. Transcriptomic analyses revealed that, in addition to the well-described ERG genes, a large group of genes encoding components of the translational apparatus along with membrane proteins were responsive to Upc2A. These Upc2A-regulated membrane protein-encoding genes are often targets of the Pdr1 transcription factor, demonstrating the high degree of overlap between these two regulatory networks. Finally, we provide evidence that Upc2A impacts the Pdr1-Cdr1 system and also modulates resistance to caspofungin. These studies provide a new perspective of Upc2A as a master regulator of lipid and membrane protein biosynthesis.https://doi.org/10.1371/journal.pgen.1009582 |
| spellingShingle | Bao Gia Vu Mark A Stamnes Yu Li P David Rogers W Scott Moye-Rowley The Candida glabrata Upc2A transcription factor is a global regulator of antifungal drug resistance pathways. PLoS Genetics |
| title | The Candida glabrata Upc2A transcription factor is a global regulator of antifungal drug resistance pathways. |
| title_full | The Candida glabrata Upc2A transcription factor is a global regulator of antifungal drug resistance pathways. |
| title_fullStr | The Candida glabrata Upc2A transcription factor is a global regulator of antifungal drug resistance pathways. |
| title_full_unstemmed | The Candida glabrata Upc2A transcription factor is a global regulator of antifungal drug resistance pathways. |
| title_short | The Candida glabrata Upc2A transcription factor is a global regulator of antifungal drug resistance pathways. |
| title_sort | candida glabrata upc2a transcription factor is a global regulator of antifungal drug resistance pathways |
| url | https://doi.org/10.1371/journal.pgen.1009582 |
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