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Published on: May 21, 2020
Essential Role of CgErg6p in Maintaining Oxidative Stress Tolerance and Iron Homeostasis in Candida glabrata
Daniel Elias1, Nora Tóth Hervay1, Marek Bujdos2
1Department of Microbiology and Virology, Faculty of Natural Sciences, Comenius University in Bratislava, Ilkovicova 6, 842 15 Bratislava, Slovakia.
Abstract:
The human pathogenic fungus Candida glabrata is the second leading cause of candidemia, a life-threatening invasive mycosis. Clinical outcomes are complicated by reduced susceptibility of C. glabrata to azoles together with its ability to evolve stable resistance to both azoles and echinocandins following drug exposure. Compared to other Candida spp., C. glabrata displays robust oxidative stress resistance. In this study, we investigated the impact of CgERG6 gene deletion on the oxidative stress response in C. glabrata. CgERG6 gene encodes sterol-24-C-methyltransferase, which is involved in the final steps of ergosterol biosynthesis. Our previous results showed that the Cgerg6Δ mutant has a lower ergosterol content in its membranes. Here, we show that the Cgerg6Δ mutant displays increased susceptibility to oxidative stress inducing agents, such as menadione, hydrogen peroxide and diamide, accompanied with increased intracellular ROS production. The Cgerg6Δ mutant is not able to tolerate higher concentrations of iron in the growth media. We observed increased expression of transcription factors, CgYap1p, CgMsn4p and CgYap5p, together with increased expression of catalase encoding the CgCTA1 gene and vacuolar iron transporter CgCCC1 in the Cgerg6Δ mutant cells. However, it seems that the CgERG6 gene deletion does not influence the function of mitochondria.
Insights
Deleting the CgERG6 gene in Candida glabrata increases susceptibility to oxidative stress and iron toxicity. This finding offers insights into antifungal drug resistance mechanisms in this opportunistic pathogen.
Area of Science:
- Medical Mycology
- Molecular Biology
- Fungal Pathogenesis
Background:
- Candida glabrata is a significant cause of candidemia, often exhibiting resistance to antifungal drugs.
- This fungus possesses notable resistance to oxidative stress, a factor potentially contributing to its virulence.
- Ergosterol biosynthesis is crucial for fungal cell membrane integrity and function.
Purpose of the Study:
- To investigate the role of the CgERG6 gene in the oxidative stress response of Candida glabrata.
- To determine the effect of CgERG6 deletion on fungal susceptibility to oxidative agents and iron.
- To elucidate the molecular mechanisms underlying the oxidative stress response in C. glabrata mutants.
Main Methods:
- Gene deletion of CgERG6 in Candida glabrata.
- Assessment of mutant susceptibility to oxidative stress agents (menadione, hydrogen peroxide, diamide) and iron.
- Measurement of intracellular reactive oxygen species (ROS) levels.
- Gene expression analysis of key transcription factors and stress-response genes (CgYap1p, CgMsn4p, CgYap5p, CgCTA1, CgCCC1).
Main Results:
- The Cgerg6Δ mutant showed increased susceptibility to menadione, hydrogen peroxide, and diamide.
- Elevated intracellular ROS production was observed in the Cgerg6Δ mutant.
- The Cgerg6Δ mutant exhibited reduced tolerance to higher iron concentrations.
- Upregulation of CgYap1p, CgMsn4p, CgYap5p, CgCTA1, and CgCCC1 was detected in the Cgerg6Δ mutant.
- Mitochondrial function remained unaffected by CgERG6 gene deletion.
Conclusions:
- CgERG6 is essential for maintaining oxidative stress resistance in Candida glabrata.
- Ergosterol biosynthesis, influenced by CgERG6, plays a critical role in managing oxidative stress and iron homeostasis.
- Understanding CgERG6 function provides potential targets for novel antifungal strategies against C. glabrata infections.
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