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Bio-energetics Investigation of Candida albicans Using Real-time Extracellular Flux Analysis
Published on: March 19, 2019
Iron restriction-induced adaptations in the wall proteome of Candida albicans
Alice G Sorgo1, Stanley Brul1, Chris G de Koster1
1Swammerdam Institute for Life Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands.
Abstract:
The opportunistic fungal pathogen Candida albicans has developed various ways to overcome iron restriction in a mammalian host. Using different surface proteins, among them membrane- and wall-localized glycosylphosphatidylinositol (GPI) proteins, it can exploit iron from host haemoglobin, ferritin and transferrin. Culturing C. albicans in rich medium supplemented with the ferrous iron chelator bathophenanthroline disulfonic acid or in the minimal medium yeast nitrogen base resulted in a strong decrease of the iron content of the cells. MS analysis of the changes in the wall proteome of C. albicans upon iron restriction showed a strong increase in the levels of the GPI-modified adhesin Als3, which also serves as a ferritin receptor, and of the GPI-modified CFEM (common in fungal extracellular membranes) domain-containing proteins Csa1, Pga7, Pga10, and Rbt5. The wall levels of the GPI-modified proteins Hyr1, the adhesin Als4 and the copper- and zinc-containing superoxide dismutase Sod4 also strongly increased, whereas the levels of Tos1 (a non-GPI protein) and the GPI-modified adhesin Als2 strongly decreased. Strikingly, peptides derived from the CFEM domain of the haem-binding proteins Csa1, Pga10 and Rbt5 were capable of forming iron adduct ions during MS analysis, consistent with a key role of this domain in haem binding.
Insights
Candida albicans adapts to low iron conditions by increasing cell wall proteins, including adhesins like Als3, to capture iron from the host. These proteins, particularly those with CFEM domains, are crucial for iron acquisition.
Area of Science:
- Medical Mycology
- Molecular Biology
- Biochemistry
Background:
- The opportunistic fungal pathogen Candida albicans must acquire iron from its mammalian host to cause infection.
- Iron acquisition is essential for fungal growth and virulence.
- Candida albicans utilizes various surface proteins to scavenge iron from host sources like hemoglobin, ferritin, and transferrin.
Purpose of the Study:
- To investigate the changes in the cell wall proteome of Candida albicans under iron-restricted conditions.
- To identify specific proteins involved in iron uptake and their roles in virulence.
- To elucidate the function of glycosylphosphatidylinositol (GPI)-anchored proteins and CFEM domains in iron acquisition.
Main Methods:
- Culturing Candida albicans in iron-depleted media (rich medium with bathophenanthroline disulfonic acid or minimal medium yeast nitrogen base).
- Mass spectrometry (MS) analysis to quantify changes in the cell wall proteome.
- Analysis of protein domains, specifically the CFEM domain, for iron-binding capabilities.
Main Results:
- Iron restriction significantly decreased intracellular iron content in Candida albicans.
- Levels of several GPI-anchored proteins, including adhesins (Als3, Als4) and CFEM domain-containing proteins (Csa1, Pga7, Pga10, Rbt5), strongly increased in the cell wall.
- Als3 functions as a ferritin receptor, and CFEM domains of Csa1, Pga10, and Rbt5 are implicated in heme binding, as evidenced by iron adduct formation during MS analysis.
- Levels of Tos1 (non-GPI) and Als2 (GPI-adhesin) decreased under iron restriction.
Conclusions:
- Candida albicans upregulates specific GPI-anchored cell wall proteins, notably adhesins and CFEM-containing proteins, to enhance iron acquisition under host-imposed iron limitation.
- The CFEM domain is critical for binding host-derived iron sources like heme.
- These findings highlight the importance of cell wall remodeling and specific protein domains in the virulence strategy of Candida albicans.
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