Iron restriction-induced adaptations in the wall proteome of Candida albicans

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.

Hemoglobin Uptake by Paracoccidioides spp. Is Receptor-Mediated

“…To function as a hemoglobin receptor, a protein must be able to bind heme. It has been suggested that the CFEM domain is able to bind to ferrous and ferric iron, including the iron atom present in the center of the heme group [23], suggesting that Pb 01 Rbt5 potentially binds to heme group. Pb 01 Rbt5 heme group-binding ability and the competition between hemoglobin and hemin for the same Pb 01 Rbt5 binding sites were demonstrated using batch ligand affinity chromatography, with a hemin-resin and the Pb 01 Rbt5 recombinant protein.…”

“…After hemoglobin release, surface receptors, e.g., Rbt5 (Repressed by Tup1), Rbt51, Wap1/Csa1 ( Candida Surface Antigen), Csa2 and Pga7 (Predicted GPI-Anchored), could function in the uptake of hemoglobin [19]. Those receptors possess a CFEM domain, which is characterized by a sequence of eight spaced cysteine residues [22], that might bind heme through the iron atom [23]. It has been demonstrated that rbt5 and wap1 are transcriptionally activated during low iron conditions (10 µM) in comparison with high iron conditions (100 µM), which indicates that these encoding proteins are important in high-affinity iron uptake pathways [24].…”

Cell Wall-Related Bionumbers and Bioestimates of Saccharomyces cerevisiae and Candida albicans

“…The wall proteome of C. albicans has been extensively studied both qualitatively and quantitatively (39,43). It shows an amazing adaptability that helps the cell to adequately respond to changes in, for example, pH, temperature, hypoxic conditions, carbon source, and iron availability and to plasma membrane and wall stress (43)(44)(45)(46)(47)(48)(49). The wall proteome also reflects morphotype and contains yeast-and hypha-specific wall proteins (50).…”

Structure–function analyses of the Pth11 receptor reveal an important role for CFEM motif and redox regulation in rice blast

“…In Candida albicans, the CFEM domain-containing proteins Rbt5, Csa1 and Pga10 serve as heme/hemoglobin receptors (Weissman & Kornitzer, 2004;P erez et al, 2006. Peptides derived from the CFEM domains of these proteins are capable of binding iron to form adducts (Sorgo et al, 2013). In Candida glabrata, CgCcw14 with a CFEM domain is essential for intracellular iron maintenance, adherence and virulence (Srivastava et al, 2014).…”