The mitogen‐activated protein kinase CgHog1 is required for iron homeostasis, adherence and virulence in Candida glabrata
Open accessAbstract
Candida glabrata has emerged as a major fungal pathogen over the last two decades, although our understanding of its survival strategies inside the mammalian host remains rudimentary. An important requirement for survival in vivo is the ability to acquire critical nutrients such as iron from host niches of varied iron content. In the present study, we demonstrate for the first time that C. glabrata cells respond to high external iron levels via activation of two stress-responsive mitogen-activated protein kinases, CgHog1 and CgSlt2, and lack of either kinase results in sensitivity to the high-iron medium. Furthermore, we show that CgHOG1 deletion led to perturbed iron homeostasis (elevated intracellular iron content and high mitochondrial aconitase activity), reduced survival in macrophages and attenuated virulence in the murine model of disseminated candidiasis. Consistently, several genes implicated in iron acquisition and storage displayed deregulated expression in the Cghog1∆ mutant. Genome-wide transcriptional profiling analysis revealed upregulation of genes implicated in DNA repair, RNA processing and autophagy, and downregulation of genes related to cellular respiration and organonitrogen compound metabolism under iron-limiting conditions. In contrast, genes involved in the respiratory electron transport chain were induced under iron-replete conditions. Gene expression microarrays also identified a set of iron-responsive regulon in C. glabrata. Lastly, we present evidence for the iron-regulated expression of the major adhesin-encoding EPA1 gene, decreased histone deacetylase activity in a high-iron environment and increased adherence of iron-surplus-medium-grown C. glabrata cells to epithelial cells. Together, our findings yield novel insights into iron abundance-based regulation of transcriptional and mitogen-activated protein kinase signaling pathways in C. glabrata.
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The high osmolarity glycerol pathway is activated by sorbic acid, and its terminal MAPK CgHog1 is required for survival of weak acid and osmotic stress.
“However, the high osmolarity glycerol pathway [HOG] is known to be activated by sorbic acid, and its terminal MAPK CgHog1 is required for survival of weak acid and osmotic stress [95,96].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [96]
The iron regulon in C. glabrata comprises a set of 51 genes that undergo reciprocal regulation in response to low and high environmental iron conditions.
“The iron regulon in C. glabrata is comprised of a set of 51 genes that undergo reciprocal regulation in response to low and high environmental iron conditions [96].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [96]
Lack of CgHog1 resulted in elevated intracellular iron and mitochondrial iron content and cell death in the high-iron environment.
“With regard to signaling pathways, Hog1-mediated MAPK has been shown to be essential for survival under high iron stress, as a lack of CgHog1 resulted in elevated intracellular iron and mitochondrial iron content and cell death in the high-iron environment [96].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [96]
Hog1-mediated MAPK is essential for survival under high iron stress.
“With regard to signaling pathways, Hog1-mediated MAPK has been shown to be essential for survival under high iron stress, as a lack of CgHog1 resulted in elevated intracellular iron and mitochondrial iron content and cell death in the high-iron environment [96].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [96]
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- Authors
- Srivastava, V. K., Suneetha, K. J., & Kaur, R.
- Affiliations
- Manipal Academy of Higher Education (IN)
- Centre for DNA Fingerprinting and Diagnostics (IN)
- Corresponding author
- Kaur, Rupinder
- ORCID
- Kaur, Rupinder
- Venue
- The FEBS Journal
- Publisher
- Wiley
- Published
- 2015-03-27
- Volume
- 282
- Issue
- 11
- Pages
- 2142-2166
- ISSN
- 1742-464X (ISSN-L)
- 1742-4658
- OpenAlex
- W1995135193
- Cited by
- 33
- References
- 54
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 2 · 2022: 3 · 2021: 1 · 2020: 6 · 2019: 3 · 2018: 6 · 2017: 2 · 2016: 3 · 2015: 1
- FWCI
- 1.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- FEBS Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Department of Biotechnology, Government of India (BT/PR13289/BRB/10/745/2009, BT/PR5145/MED/29/470/2012 and BT/PR7388/MED/29/650/2012)
- Centre for DNA Fingerprinting and Diagnostics, Hyderabad
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Keywords
- Candida glabrata, Hog1, MAPK signaling, iron homeostasis, iron acquisition, macrophage survival, systemic candidiasis, virulence, cell adhesion, histone deacetylase, transcriptional regulation, mitochondrial aconitase
- MeSH terms
- Aconitate Hydratase, Animals, Candidiasis, Cell Line, Enzyme Activation, Female, Fungal Proteins, Cricetinae, Homeostasis, Mice, Inbred BALB C, Mitochondria, RNA Processing, Post-Transcriptional, Virulence, Mitogen-Activated Protein Kinases, Candida glabrata, Transcriptome, Gene Ontology
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