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Identification and functional characterization of Rca1, a transcription factor involved in both antifungal
Patrick Vandeputte1, Sylvain Pradervand, Françoise Ischer
1Institute of Microbiology, University of Lausanne and University Hospital Center, Lausanne, Switzerland.
Abstract:
The identification of novel transcription factors associated with antifungal response may allow the discovery of fungus-specific targets for new therapeutic strategies. A collection of 241 Candida albicans transcriptional regulator mutants was screened for altered susceptibility to fluconazole, caspofungin, amphotericin B, and 5-fluorocytosine. Thirteen of these mutants not yet identified in terms of their role in antifungal response were further investigated, and the function of one of them, a mutant of orf19.6102 (RCA1), was characterized by transcriptome analysis. Strand-specific RNA sequencing and phenotypic tests assigned Rca1 as the regulator of hyphal formation through the cyclic AMP/protein kinase A (cAMP/PKA) signaling pathway and the transcription factor Efg1, but also probably through its interaction with a transcriptional repressor, most likely Tup1. The mechanisms responsible for the high level of resistance to caspofungin and fluconazole observed resulting from RCA1 deletion were investigated. From our observations, we propose that caspofungin resistance was the consequence of the deregulation of cell wall gene expression and that fluconazole resistance was linked to the modulation of the cAMP/PKA signaling pathway activity. In conclusion, our large-scale screening of a C. albicans transcription factor mutant collection allowed the identification of new effectors of the response to antifungals. The functional characterization of Rca1 assigned this transcription factor and its downstream targets as promising candidates for the development of new therapeutic strategies, as Rca1 influences host sensing, hyphal development, and antifungal response.
Insights
Researchers identified new transcription factors in Candida albicans that affect antifungal drug response. One factor, Rca1, regulates fungal development and resistance, offering potential targets for novel antifungal therapies.
Area of Science:
- Microbiology
- Molecular Biology
- Drug Discovery
Background:
- Identifying novel targets for antifungal therapies is crucial for combating drug-resistant fungal infections.
- Transcription factors play a key role in regulating fungal responses to environmental stress, including antifungal drugs.
Purpose of the Study:
- To screen a collection of Candida albicans transcription factor mutants for altered susceptibility to common antifungal drugs.
- To functionally characterize novel transcription factors involved in antifungal response and identify potential therapeutic targets.
Main Methods:
- Large-scale screening of 241 Candida albicans transcriptional regulator mutants against fluconazole, caspofungin, amphotericin B, and 5-fluorocytosine.
- Transcriptome analysis (strand-specific RNA sequencing) and phenotypic tests to characterize the function of the orf19.6102 (RCA1) mutant.
- Investigation of the mechanisms underlying caspofungin and fluconazole resistance in RCA1 deletion mutants.
Main Results:
- Thirteen novel mutants with altered antifungal susceptibility were identified.
- Rca1 was characterized as a regulator of hyphal formation via the cyclic AMP/protein kinase A (cAMP/PKA) pathway and Efg1, potentially interacting with Tup1.
- RCA1 deletion resulted in high resistance to caspofungin (linked to cell wall gene expression deregulation) and fluconazole (linked to cAMP/PKA pathway modulation).
Conclusions:
- A large-scale screen identified new effectors of antifungal response in Candida albicans.
- The transcription factor Rca1 and its downstream targets are promising candidates for developing new antifungal therapeutic strategies.
- Rca1 influences host sensing, hyphal development, and antifungal drug response, highlighting its potential as a therapeutic target.
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