A novel role for the transcription factor Cwt1p as a negative regulator of nitrosative stress in Candida albicans
Adnane Sellam1, Faiza Tebbji, Malcolm Whiteway
1Institute for Research in Immunology and Cancer, University of Montreal, Montréal, QC, Canada. adnane.sellam@gmail.com
Abstract:
The ability of Candida albicans to survive in the presence of nitrosative stress during the initial contact with the host immune system is crucial for its ability to colonize mammalian hosts. Thus, this fungus must activate robust mechanisms to neutralize and repair nitrosative-induced damage. Until now, very little was known regarding the regulatory circuits associated with reactive nitrogen species detoxification in fungi. To gain insight into the transcriptional regulatory networks controlling nitrosative stress response (NRS) in C. albicans a compilation of transcriptional regulator-defective mutants were screened. This led to the identification of Cwt1p as a negative regulator of NSR. By combining genome-wide location and expression analyses, we have characterized the Cwt1p regulon and demonstrated that Cwt1p is directly required for proper repression of the flavohemoglobin Yhb1p, a key NO-detoxification enzyme. Furthermore, Cwt1p operates both by activating and repressing genes of specific functions solicited upon NSR. Additionally, we used Gene Set Enrichment Analysis to reinvestigate the C. albicans NSR-transcriptome and demonstrate a significant similarity with the transcriptional profiles of C. albicans interacting with phagocytic host-cells. In summary, we have characterized a novel negative regulator of NSR and bring new insights into the transcriptional regulatory network governing fungal NSR.
Insights
Candida albicans uses Cwt1p to control its response to nitrosative stress, a key factor in fungal colonization. This study identifies Cwt1p as a negative regulator essential for detoxifying reactive nitrogen species.
Area of Science:
- Microbiology
- Mycology
- Molecular Biology
Background:
- Candida albicans colonization requires survival under nitrosative stress from host immune responses.
- Fungal detoxification mechanisms for reactive nitrogen species (RNS) and their regulation are poorly understood.
- Understanding nitrosative stress response (NSR) is critical for fungal pathogenesis.
Purpose of the Study:
- To identify transcriptional regulators controlling nitrosative stress response (NSR) in Candida albicans.
- To characterize the role of Cwt1p in regulating NSR and RNS detoxification.
- To elucidate the regulatory network governing fungal NSR.
Main Methods:
- Screening of transcriptional regulator-defective mutants in C. albicans.
- Genome-wide location and expression analyses to define the Cwt1p regulon.
- Gene Set Enrichment Analysis (GSEA) of the NSR-transcriptome.
Main Results:
- Cwt1p was identified as a negative regulator of NSR in C. albicans.
- Cwt1p directly represses the flavohemoglobin Yhb1p, a crucial NO-detoxification enzyme.
- Cwt1p regulates both activation and repression of genes involved in NSR.
- C. albicans NSR transcriptional profiles resemble those during interaction with phagocytic host cells.
Conclusions:
- Cwt1p is a novel negative regulator of nitrosative stress response in C. albicans.
- This study reveals new insights into the transcriptional regulatory network governing fungal NSR.
- Understanding Cwt1p's role may offer targets for controlling C. albicans infections.
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