Structural basis for activation of fungal sterol receptor Upc2 and azole resistance
Abstract
Fungal transcription factor Upc2 senses ergosterol levels and regulates sterol biosynthesis and uptake. Constitutive activation of Upc2 causes azole resistance in Candida species. We determined the structure of ergosterol-bound Upc2, revealing the ligand specificity and transcriptional regulation. Ergosterol binding involves conformational changes of the ligand-binding domain, creating a shape-complementary hydrophobic pocket. The conserved helix α12 and glycine-rich loop are critical for sterol recognition by forming the pocket wall. The mutations of the glycine-rich loop inhibit ligand binding by steric clashes and constitutively activate Upc2. The translocation of Upc2 is regulated by Hsp90 chaperone in a sterol-dependent manner. Ergosterol-bound Upc2 associates with Hsp90 using the C-terminal tail, which retains the inactive Upc2 in the cytosol. Ergosterol dissociation induces a conformational change of the C-terminal tail, releasing Upc2 from Hsp90 for nuclear transport by importin α. The understanding of the regulatory mechanism provides an antifungal target for the treatment of azole-resistant Candida infections.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the nucleus, the DBD of Upc2 binds to SREs in promoter regions and activates transcription of ERGs.
“Once inside the nucleus, the DBD of Upc2 binds to sterol response elements (SREs) located in the promoter regions, thereby activating the transcription of ergosterol biosynthesis genes (ERGs) [14].”
From Disruption of the UPC2 Gene Enhances Fluconazole Antifungal Activity by Inhibiting HAC1 mRNA Splicing in Candida albicans (2026) · cites this paper as [14]
The conformational change in Upc2 facilitates dissociation of Hsp90 from Upc2.
“This conformational change facilitates the dissociation of Hsp90 from Upc2.”
From Disruption of the UPC2 Gene Enhances Fluconazole Antifungal Activity by Inhibiting HAC1 mRNA Splicing in Candida albicans (2026) · cites this paper as [14]
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 [14]
Azole exposure reduces ergosterol levels, causing ergosterol to dissociate from Upc2 and inducing conformational changes in its C-terminal activation loop.
“Upon C. albicans’ exposure to azoles, which cause a reduction in ergosterol levels, ergosterol dissociates from Upc2, inducing conformational changes in the C-terminal activation loop.”
From Disruption of the UPC2 Gene Enhances Fluconazole Antifungal Activity by Inhibiting HAC1 mRNA Splicing in Candida albicans (2026) · cites this paper as [14]
Srp1 binds to the NLS of free Upc2 and mediates its transport into the nucleus.
“Subsequently, the nuclear importin Srp1 binds to the NLS of the now free Upc2, mediating its transport into the nucleus.”
From Disruption of the UPC2 Gene Enhances Fluconazole Antifungal Activity by Inhibiting HAC1 mRNA Splicing in Candida albicans (2026) · cites this paper as [14]
Upc2 senses intracellular ergosterol levels and regulates biosynthesis and uptake of ergosterol, contributing to azole resistance in Candida species.
“Tan et al. demonstrated that Upc2 is capable of sensing intracellular ergosterol levels in fungi, subsequently regulating both the biosynthesis and uptake of ergosterol, which contributes to azole resistance in Candida species [14].”
From Disruption of the UPC2 Gene Enhances Fluconazole Antifungal Activity by Inhibiting HAC1 mRNA Splicing in Candida albicans (2026) · cites this paper as [14]
Hsp90 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 [14]
The Upc2 LBD exhibits ligand-dependent conformational switching and mutations of the glycine-rich loop interfere with ligand binding via steric clashes, resulting in constitutive activation.
“The Upc2 LBD exhibits ligand-dependent conformational switching and mutations of the glycine-rich loop interfere with ligand binding via steric clashes, resulting in constitutive activation26.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [26]
The citation lists haven’t been fetched yet
References 37 · Cited by 38
- Authors
- Tan, L., Chen, L., Yang, H., Jin, B., Kim, G., & Im, Y. J.
- Affiliations
- Chonnam National University (KR)
- Corresponding author
- Im, Young Jun
- Venue
- Nature Chemical Biology
- Published
- 2022-10-13
- Volume
- 18
- Issue
- 11
- Pages
- 1253-1262
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W4305015464
- Cited by
- 38
- References
- 37
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 19 · 2023: 3
- FWCI
- 3.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Research Foundation of Korea (2019R1A2C1085530)
- Korea Health Industry Development Institute (HI20C0079)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- UPC2, ergosterol, azole resistance, Candida, transcriptional activation, ligand binding, Hsp90 chaperone, nuclear import, importin alpha, sterol biosynthesis, antifungal drug targets, protein structure
- MeSH terms
- Antifungal Agents, Azoles, Ergosterol, Fungal Proteins, Glycine, Ligands, Sterols, Transcription Factors, Gene Expression Regulation, Fungal, HSP90 Heat-Shock Proteins, Drug Resistance, Fungal, alpha Karyopherins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
