A family of Candida cell surface haem‐binding proteins involved in haemin and haemoglobin‐iron utilization

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Abstract
The ability to acquire iron from host tissues is a major virulence factor of pathogenic microorganisms. Candida albicans is an important fungal pathogen, responsible for an increasing proportion of systemic infections. C. albicans, like many pathogenic bacteria, is able to utilize haemin and haemoglobin as iron sources. However, the molecular basis of this pathway in pathogenic fungi is unknown. Here, we identify a conserved family of plasma membrane-anchored proteins as haem-binding proteins that are involved in haem-iron utilization. We isolated RBT51 as a gene that is sufficient by itself to confer to S. cerevisiae the ability to utilize haemoglobin iron. RBT51 is highly homologous to RBT5, which was previously identified as a gene negatively regulated by the transcriptional suppressor CaTup1. Rbt5 and Rbt51 are mannosylated proteins that carry the conserved CFEM domain. We find that RBT5 is strongly induced by starvation for iron, and that deletion of RBT5 is by itself sufficient to significantly reduce the ability of C. albicans to utilize haemin and haemoglobin as iron sources. Iron starvation-inducible, antigenically cross-reacting haem-binding proteins are also present in other Candida species that are able to utilize haem-iron, underscoring the conservation of this iron acquisition pathway among pathogenic fungi.