A systematic analysis reveals an essential role for high-affinity iron uptake system, haemolysin and CFEM domain-containing protein in iron homoeostasis and virulence in Candida glabrata
Abstract
Iron is an essential nutrient for all living organisms and human pathogens employ a battery of factors to scavenge iron from the high-affinity iron-binding host proteins. In the present study, we have elucidated, via a candidate gene approach, major iron acquisition and homoeostatic mechanisms operational in an opportunistic human fungal pathogen Candida glabrata. Phenotypic, biochemical and molecular analysis of a set of 13 C. glabrata strains, deleted for proteins potentially implicated in iron metabolism, revealed that the high-affinity reductive iron uptake system is required for utilization of alternate carbon sources and for growth under both in vitro iron-limiting and in vivo conditions. Furthermore, we show for the first time that the cysteine-rich CFEM (common in fungal extracellular membranes) domain-containing cell wall structural protein, CgCcw14, and a putative haemolysin, CgMam3, are essential for maintenance of intracellular iron content, adherence to epithelial cells and virulence. Consistent with their roles in iron homoeostasis, mitochondrial aconitase activity was lower and higher in mutants disrupted for high-affinity iron transport, and haemolysin respectively. Additionally, we present evidence that the mitochondrial frataxin, CgYfh1, is pivotal to iron metabolism. Besides yielding insights into major in vitro and in vivo iron acquisition strategies, our findings establish high-affinity iron uptake mechanisms as critical virulence determinants in C. glabrata.
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High-affinity iron uptake mechanisms are critical virulence determinants in C. glabrata.
“Additionally, they present evidence that the mitochondrial frataxin CgYfh1 is pivotal to Fe metabolism and conclude that high-affinity iron uptake mechanisms are critical virulence determinants in C. glabrata [78].”
From Strategies of intracellular pathogens for obtaining iron from the environment (2015) · cites this paper as [78]
The high-affinity reductive iron uptake system is necessary for metabolism in the presence of alternate carbon sources and for growth under in vitro and in vivo iron-limiting conditions.
“According to the findings of Srivastava et al. [50] that the high-affinity reductive iron uptake system is necessary for metabolism in the presence of alternate carbon sources and for growth under both in vitro and in vivo iron-limiting conditions.”
From Candida glabrata: pathogenicity and resistance mechanisms for adaptation and survival (2021) · cites this paper as [50]
The reductive iron acquisition system in C. glabrata consists of three ferric reductases, multicopper ferroxidase CgFet3, iron transporter/permease CgFtr1, and copper ion transporter CgCcc2.
“The reductive iron acquisition system in C. glabrata consists of three ferric reductases, multicopper ferroxidase CgFet3 (oxidizes Fe2+ to Fe3+), an iron transporter/permease CgFtr1 (facilitates the passage of Fe3+ across the membrane) and a copper ion transporter CgCcc2 (loads copper on to CgFet3) [122].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [122]
All known fungal iron uptake mechanisms except receptor-mediated haem uptake are operational in C. glabrata.
“Of known fungal iron uptake mechanisms, siderophore-mediated uptake of Fe3+, reductive iron acquisition, haemoglobin/haem uptake [120], all systems are operational in C. glabrata except for the receptor-mediated haem uptake [121,122].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [122]
Disruption of the high-affinity iron uptake components debilitated survival under in vitro iron-limiting conditions.
“Disruption of the high-affinity iron uptake components resulted in perturbed iron homoeostasis, debilitated survival under in vitro iron-limiting conditions and attenuated virulence [122].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [122]
Putative CFEM domain-containing protein CgCcw14, haem oxygenase CgHmx1, and intracellular iron trafficking machinery components including vacuolar and mitochondrial iron transporters have been identified in C. glabrata.
“Recently, putative cell surface-associated, cysteine-rich Common in Fungal Extracellular Membrane (CFEM) domain-containing protein (CgCcw14), haem oxygenase (CgHmx1) and intracellular iron trafficking machinery components including vacuolar (CgCcc1, CgSmf1, CgSmf3, and CgFth1) and mitochondrial (CgMmt1, CgMmt2, CgAtm1, CgMrs3, and CgMrs4) iron transporters have been identified in C. glabrata [122,”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [122]
C. glabrata lacks the haem receptor.
“Although C. glabrata exhibits haemolytic activity in vitro and possesses hemolysins, it lacks the haem receptor [121,122,124].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [122]
Disruption of the high-affinity iron uptake components resulted in perturbed iron homeostasis.
“Disruption of the high-affinity iron uptake components resulted in perturbed iron homoeostasis, debilitated survival under in vitro iron-limiting conditions and attenuated virulence [122].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [122]
C. glabrata exhibits haemolytic activity in vitro and possesses hemolysins.
“Although C. glabrata exhibits haemolytic activity in vitro and possesses hemolysins, it lacks the haem receptor [121,122,124].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [122]
Disruption of the high-affinity iron uptake components attenuated virulence.
“Disruption of the high-affinity iron uptake components resulted in perturbed iron homoeostasis, debilitated survival under in vitro iron-limiting conditions and attenuated virulence [122].”
From Candida glabrata: A Lot More Than Meets the Eye (2019) · cites this paper as [122]
The study confirmed important roles of FTR1, FET3, YFH1, and ATM1 in iron homeostasis.
“We were able to confirm the important roles of various iron-associated genes described previously in C. glabrata, such as FTR1, FET3, and YFH1 (40), or in C. albicans and S. cerevisiae, such as ATM1 (29, 31).”
From A novel hybrid iron regulation network combines features from pathogenic and nonpathogenic yeasts (2016) · cites this paper as [40]
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- Authors
- Srivastava, V. K., Suneetha, K. J., & Kaur, R.
- Affiliations
- Centre for DNA Fingerprinting and Diagnostics (IN)
- ORCID
- Kaur, Rupinder
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2014-09-08
- Volume
- 463
- Issue
- 1
- Pages
- 103-114
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- OpenAlex
- W2054716142
- Semantic Scholar
- 37379a8ad82fb09c6ae66d018abb3d9d6be3564f
- Cited by
- 69
- References
- 61
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 11 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 13 · 2019: 7 · 2018: 2 · 2017: 6 · 2016: 5 · 2015: 4 · 2014: 2
- FWCI
- 2.33
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- 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, iron homeostasis, high-affinity iron uptake, hemolysin, frataxin, mitochondrial aconitase, fungal virulence, iron acquisition, epithelial cell adherence, opportunistic fungal pathogens
- MeSH terms
- Frataxin, Aconitate Hydratase, Candidiasis, Fungal Proteins, Hemolysin Proteins, Homeostasis, Humans, Iron, Gene Deletion, Mitochondrial Proteins, Iron-Binding Proteins, Candida glabrata
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