Structural mechanism of ergosterol regulation by fungal sterol transcription factor Upc2
Open accessAbstract
Transcriptional regulation of ergosterol biosynthesis in fungi is crucial for sterol homeostasis and for resistance to azole drugs. In Saccharomyces cerevisiae, the Upc2 transcription factor activates the expression of related genes in response to sterol depletion by poorly understood mechanisms. We have determined the structure of the C-terminal domain (CTD) of Upc2, which displays a novel α-helical fold with a deep hydrophobic pocket. We discovered that the conserved CTD is a ligand-binding domain and senses the ergosterol level in the cell. Ergosterol binding represses its transcription activity, while dissociation of the ligand leads to relocalization of Upc2 from cytosol to nucleus for transcriptional activation. The C-terminal activation loop is essential for ligand binding and for transcriptional regulation. Our findings highlight that Upc2 represents a novel class of fungal zinc cluster transcription factors, which can serve as a target for the developments of antifungal therapeutics. In yeast, the transcription factor Upc2 regulates genes involved in ergosterol biosynthesis, but how its activity is regulated is unknown. Here Yang et al. present the structure of the Upc2 C-terminal domain and discover that it functions as a sensor of the ergosterol level, regulating the transcriptional activity and cellular localization of Upc2.
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Under normal intracellular ergosterol levels, ergosterol associates with the LBD of Upc2 and Hsp90 interacts with its activation loop, retaining Upc2 in the cytoplasm.
“Under conditions of normal intracellular ergosterol levels, ergosterol associates with the LBD, while Hsp90 interacts with the activation loop of Upc2, resulting in its retention within the cytoplasm [13,14].”
From Disruption of the UPC2 Gene Enhances Fluconazole Antifungal Activity by Inhibiting HAC1 mRNA Splicing in Candida albicans (2026) · cites this paper as [13]
The Results and Discussion state that ergosterol binds the Upc2 LBD and that ergosterol-bound Upc2 remains in the cytosol under sterol-rich conditions. The Discussion says the relationship between Hsp90 and Upc2 requires further investigation; it does not establish that Hsp90 interacts with Upc2’s activation loop or causes its cytoplasmic retention. Page numbers are unavailable in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredHsp90 physically interacts with Upc2 and regulates its transcriptional activity.
“This observation aligns with previous studies that have shown Hsp90 to physically interact with Upc2 and regulate its transcriptional activity [13,14].”
From Disruption of the UPC2 Gene Enhances Fluconazole Antifungal Activity by Inhibiting HAC1 mRNA Splicing in Candida albicans (2026) · cites this paper as [13]
The Discussion (page unavailable) reports a genetic interaction between Hsp90 and Upc2 and says Hsp90-mediated morphogenesis occurs via Upc2. It does not establish that Hsp90 physically interacts with Upc2 or regulates Upc2’s transcriptional activity; it says their relationship requires further investigation. (LLM, conf=0.85)
Experimental — accuracy not yet measuredUpc2 is a global ergosterol-synthesis-related gene regulator contributing to FLC tolerance.
“Upc2 is a global ergosterol-synthesis-related gene regulator contributing to FLC tolerance [40,41].”
From Pitavastatin Calcium Confers Fungicidal Properties to Fluconazole by Inhibiting Ubiquinone Biosynthesis and Generating Reactive Oxygen Species (2024) · cites this paper as [41]
Upc2 is a pivotal transcription factor regulating ergosterol biosynthesis in Candida albicans.
“Upc2 serves as a pivotal transcription factor in the regulation of ergosterol biosynthesis.”
From Disruption of the UPC2 Gene Enhances Fluconazole Antifungal Activity by Inhibiting HAC1 mRNA Splicing in Candida albicans (2026) · cites this paper as [13]
There are no gain-of-function forms currently known for UPC2A.
“there are no gain-of-function (GOF) forms currently known for UPC2A.”
From The Candida glabrata Upc2A transcription factor is a global regulator of antifungal drug resistance pathways (2021) · cites this paper as [22]
Upc2A appears to accumulate inside the nucleus upon ergosterol limitation where it binds to SRE-containing promoters.
“These data agree with the model proposed earlier for ScUpc2 that Upc2A appeared to accumulate inside the nucleus upon ergosterol limitation where the factor then binds to SRE-containing promoters [22].”
From The Candida glabrata Upc2A transcription factor is a global regulator of antifungal drug resistance pathways (2021) · cites this paper as [22]
The DNA-binding activity of wild-type but not G898D Upc2A is increased by fluconazole, possibly by an increase in nuclear localization.
“these data support the view that the DNA-binding activity of wild-type but not G898D Upc2A is increased by the presence of fluconazole, possibly by an increase in nuclear localization [22].”
From The Candida glabrata Upc2A transcription factor is a global regulator of antifungal drug resistance pathways (2021) · cites this paper as [22]
C. glabrata Upc2A accumulates in the nucleus upon ergosterol limitation.
“Based on detailed structural and subcellular localization studies on S. cerevisiae Upc2 [22], we propose that C. glabrata Upc2A accumulates in the nucleus upon ergosterol limitation.”
From The Candida glabrata Upc2A transcription factor is a global regulator of antifungal drug resistance pathways (2021) · cites this paper as [22]
Dimerization is essential for Upc2 regulatory function, as its disruption traps the transcription factor in the cytosol.
“Dimerization is essential for Upc2 regulatory function, as its disruption traps the transcription factor in the cytosol [71].”
From Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae (2020) · cites this paper as [71]
The carboxy-terminal domain (CTD) of yeast Upc2 displays a novel α-helical fold and serves as an ergosterol-binding and sensing domain.
“The recent elucidation of the structure of the carboxy-terminal domain (CTD) of yeast Upc2, which displays a novel α-helical fold, has demonstrated that it serves as an ergosterol-binding and sensing domain (Figure 2A) [71].”
From Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae (2020) · cites this paper as [71]
Under normal conditions, the binding of ergosterol to a deep hydrophobic pocket within Upc2 CTD retains the transcription factor in the cytosol in its repressed form.
“Under normal conditions, the binding of ergosterol to a deep hydrophobic pocket within Upc2 CTD retains the transcription factor in the cytosol in its repressed form, probably because sterol binding masks its bipartite amino-terminal nuclear localization signal (NLS) or because of its interaction with a hypothetical cytosolic protein (Figure 2B) [71,72].”
From Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae (2020) · cites this paper as [71]
Size-exclusion chromatography analyses strongly suggest that the biologically relevant form of Upc2 is a constitutive homodimer, which is assembled through its carboxy-terminal sterol-binding domain.
“Moreover, size-exclusion chromatography analyses strongly suggest that the biologically relevant form of Upc2 is a constitutive homodimer, which is assembled through its carboxy-terminal sterol-binding domain (Figure 2B) [71].”
From Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae (2020) · cites this paper as [71]
Upon ergosterol depletion, the dissociation of the sterol ligand causes a conformational change that exposes Upc2 NLS, causing its translocation to the nucleus, where it activates the transcription of SRE/AR1c-containing genes including most ERG genes, sterol uptake genes (AUS1, PDR11), the DAN/TIR genes, and members of the PAU gene family.
“Upon ergosterol depletion, the dissociation of the sterol ligand causes a conformational change that exposes Upc2 NLS, causing its translocation to the nucleus, where it activates the transcription of SRE/AR1c-containing genes including most ERG genes, sterol uptake genes (AUS1, PDR11), the DAN/TIR genes, which encode nine cell wall mannoproteins, and members of the seripauperin (PAU) gene family”
From Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae (2020) · cites this paper as [71]
These transcriptional responses have been shown to be dependent on the presence of the azoles and/or depletion of ergosterol.
“To date, these transcriptional responses have been shown to be dependent on the presence of the azoles and/or depletion of ergosterol.”
From Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles (2018) · cites this paper as Yang et al., 2015
Several lines of evidence suggest that ergosterol depletion might be a cause of azole-activated transcriptional responses by ergosterol biosynthesis genes.
“For azole-activated transcriptional responses by genes for ergosterol biosynthesis, several lines of evidence suggest that ergosterol depletion might be a cause.”
From Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles (2018) · cites this paper as Yang et al., 2015
In S. cerevisiae, transcription factor Upc2p regulates expression of ergosterol biosynthesis genes, directly interacts with ergosterol, and its activity is regulated by ergosterol levels.
“In S. cerevisiae, transcription factor Upc2p regulates expression of ergosterol biosynthesis genes. Upc2p directly interacts with ergosterol and its activity was regulated by ergosterol levels (Yang et al., 2015).”
From Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles (2018) · cites this paper as Yang et al., 2015
All above lines of evidence suggest that ergosterol depletion resulted from azole stress might be a cause for the transcriptional responses by ergosterol biosynthesis genes, but some direct experimental data in other fungi are still required for making a definite conclusion.
“All above lines of evidence suggest that ergosterol depletion resulted from azole stress might be a cause for the transcriptional responses by ergosterol biosynthesis genes, but some direct experimental data in other fungi are still required for making a definite conclusion.”
From Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles (2018) · cites this paper as Yang et al., 2015
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Linkage between genes involved in azole resistance and ergosterol biosynthesis
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Lu, H., Li, W., Whiteway, M., Wang, H., Zhu, S., Ji, Z., Feng, Y., Yan, L., Fang, T., Li, L., et al. (2023) · mBio · doi:10.1128/mbio.02639-22 · Cited by 30 · see citing works
Zhen, C., Wang, L., Feng, Y., Whiteway, M., Hang, S., Yu, J., Lu, H., & Jiang, Y. (2024) · Advanced Science · doi:10.1002/advs.202406473 · Cited by 16 · see citing works
Li, W., Feng, Y., Feng, Z., Wang, L., Whiteway, M., Lu, H., & Jiang, Y. (2024) · Antioxidants · doi:10.3390/antiox13060667 · Cited by 14 · see citing works
“Upc2 is a global ergosterol-synthesis-related gene regulator contributing to FLC tolerance [40,41].”
BackgroundYu, J., Jiang, B., Xiong, J., Xu, X., Xu, L., Jiang, Y., & Lu, H. (2026) · Pathogens · doi:10.3390/pathogens15060629 · Cited by 2 · see citing works
“Structurally, Upc2 comprises a nuclear localization signal (NLS) at its N-terminus, a DNA-binding domain (DBD), a ligand-binding domain (LBD) at its C-terminus, and an activation loop [13].”
- Authors
- Yang, H., Tong, J., Lee, C. W., Ha, S., Eom, S. H., & Im, Y. J.
- Affiliations
- Chonnam National University (KR)
- Gwangju Institute of Science and Technology (KR)
- Corresponding author
- Im, Young Jun
- Venue
- Nature Communications
- Published
- 2015-02-06
- Volume
- 6
- Issue
- 1
- Pages
- 6129-6129
- ISSN
- 2041-1723 (ISSN-L)
- OpenAlex
- W1991460906
- Cited by
- 223
- References
- 56
- Citations by year
- 2026: 22 · 2025: 29 · 2024: 25 · 2023: 22 · 2022: 26 · 2021: 21 · 2020: 22 · 2019: 19 · 2018: 16 · 2017: 12 · 2016: 4 · 2015: 5
- FWCI
- 5.35
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Research Foundation
- National Research Foundation of Korea (NRF-2010-0013448)
- Ministry of Education, Science and Technology (NRF-2010-0013448, NRF-2014R1A1A1003060)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- UPC2, ergosterol biosynthesis, sterol homeostasis, zinc cluster transcription factors, ligand-binding domain, transcriptional regulation, sterol sensing, nuclear relocalization, activation loop, antifungal resistance, azole resistance, Saccharomyces cerevisiae
- MeSH terms
- Antifungal Agents, Binding Sites, Cell Nucleus, Chromatography, Gel, Chromatography, High Pressure Liquid, Cytosol, Drug Resistance, Microbial, Ergosterol, Ligands, Models, Biological, Reference Standards, Saccharomyces cerevisiae, Spectrometry, Fluorescence, Mass Spectrometry, Trans-Activators, Fluconazole, Zinc Fingers, Protein Structure, Secondary, Protein Structure, Tertiary, Crystallography, X-Ray, Saccharomyces cerevisiae Proteins, Green Fluorescent Proteins, Mutant Proteins, Protein Multimerization, Chromatography, Reverse-Phase
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