De-repression of CSP-1 activates adaptive responses to antifungal azoles.
Open accessAbstract
Antifungal azoles are the major drugs that are used to treat fungal infections. This study found that in response to antifungal azole stress, Neurospora crassa could activate the transcriptional responses of many genes and increase azole resistance by reducing the level of conidial separation 1 (CSP-1), a global transcription repressor, at azole-responsive genes. The expression of csp-1 was directly activated by the transcription factors WC-1 and WC-2. Upon ketoconazole (KTC) stress, the transcript levels of wc-1 and wc-2 were not changed, but csp-1 transcription rapidly declined. A chromatin immunoprecipitation-quantitative polymerase chain reaction analysis revealed a rapid reduction in the WC-2 enrichment at the csp-1 promoter upon KTC treatment, which might be responsible for the KTC-induced csp-1 downregulation. Deletion of csp-1 increased resistance to KTC and voriconazole, while csp-1 overexpression increased KTC susceptibility. CSP-1 transcriptionally repressed a number of azole-responsive genes, including genes encoding the azole target ERG11, the azole efflux pump CDR4, and the sterol C-22 desaturase ERG5. Deletion of csp-1 also reduced the KTC-induced accumulation of ergosterol intermediates, eburicol, and 14α-methyl-3,6-diol. CSP-1 orthologs are widely present in filamentous fungi, and an Aspergillus fumigatus mutant in which the csp-1 was deleted was resistant to itraconazole.
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Antifungal azoles block ergosterol biosynthesis by inhibiting sterol 14α-demethylase.
“Antifungal azoles block ergosterol biosynthesis by inhibiting sterol 14α-demethylase.”
From Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles (2018) · cites this paper as Chen et al., 2016
Azole inhibition of sterol 14α-demethylase commonly leads to depletion of ergosterol and accumulation of other sterols, including lanosterol, eburicol and 14α-methyl-3,6-diol, within fungal cell membranes.
“Inhibition by azoles commonly leads to depletion of ergosterol and accumulation of other sterols, such as lanosterol, eburicol and the toxic 14α-methyl-3,6-diol, within fungal cell membranes (Watson et al., 1989; Shapiro et al., 2011; Chen et al., 2016).”
From Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles (2018) · cites this paper as Chen et al., 2016
In Ptcu-1::erg11 treated with CuSO4, ergosterol was reduced to approximately 56% of BCS-treated levels and lanosterol, eburicol and 14α-methyl-3,6-diol accumulated, similar to azole-treated N. crassa.
“CuSO4 treatment resulted in the reduction of ergosterol to a level of approximately 56% of that treated with BCS along with the accumulation of lanosterol, eburicol and 14α-methyl-3,6-diol, similar to that found in N. crassa treated with azoles (Chen et al., 2016).”
From Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles (2018) · cites this paper as Chen et al., 2016
Inhibition or inactivation of erg11 causes accumulation of lanosterol, eburicol and the toxic sterol 14α-methyl-3,6-diol.
“As inhibition or inactivation of erg11 causes accumulation of lanosterol, eburicol and the toxic sterol 14α-methyl-3,6-diol (Watson et al., 1989; Chen et al., 2016) (Supplementary Figure 4 and Supplementary Table 4)”
From Abnormal Ergosterol Biosynthesis Activates Transcriptional Responses to Antifungal Azoles (2018) · cites this paper as Chen et al., 2016
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- Authors
- Chen, X., Xue, W., Zhou, J., Zhang, Z., Wei, S., Liu, X., Sun, X., Wang, W., & Li, S.
- Affiliations
- Chinese Academy of Sciences (CN)
- China University of Geosciences (Beijing) (CN)
- Corresponding author
- Li, Shaojie
- ORCID
- Venue
- Scientific Reports
- Published
- 2016-01-19
- Volume
- 6
- Issue
- 1
- Pages
- 19447-19447
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4726075
- OpenAlex
- W2396581426
- Cited by
- 20
- References
- 43
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 1 · 2022: 2 · 2020: 2 · 2019: 1 · 2018: 4 · 2017: 2 · 2016: 1
- FWCI
- 1.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (31461143002, 31371986)
- 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 › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Keywords
- Neurospora crassa, azole antifungals, azole resistance, ketoconazole, voriconazole, WC1, transcriptional repression, ERG11, ergosterol biosynthesis, Aspergillus fumigatus, itraconazole resistance, transcriptional response
- MeSH terms
- Antifungal Agents, Aspergillus fumigatus, Azoles, Fungal Proteins, Neurospora crassa, Promoter Regions, Genetic, Protein Binding, Transcription, Genetic, Down-Regulation, Gene Expression, Gene Expression Regulation, Fungal, Gene Deletion, Drug Resistance, Fungal
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