Iron acquisition represents a challenge for all organisms due to the low solubility of iron under oxidizing conditions. This challenge is particularly acute for pathogenic microorganisms, due to the iron withholding mechanisms deployed by the host. Many microbial pathogens have therefore evolved mechanisms to extract iron from hemoglobin, the largest iron store in the host, by removing the heme cofactor from the globins and transferring it to the microbe’s cytoplasm. The fungal pathogen Candida albicans uses a family of conserved extracellular proteins for that purpose, the CFEM proteins. The cell wall-anchored CFEM proteins Rbt5 and Pga7 and the secreted CFEM protein Csa2 are all able to extract heme from hemoglobin. The heme can then subsequently be transferred from one CFEM protein to the next until it reaches the plasma membrane, whereupon it is endocytosed by a mechanism involving the ESCRT pathway. Analysis of the fungal CFEM heme-acquisition pathway reveals that it is unrelated, at either the sequence or structure level, to the known bacterial heme-acquisition pathways, indicating that microbes have evolved several different independent solutions to the iron acquisition problem.
