Heme-iron acquisition in fungi

To overcome iron-withholding defenses deployed by the host, many microbial pathogens have evolved mechanisms for extracting iron from hemoglobin, the largest iron store in the host. Fungi, including the pathogen Candida albicans,contain a heme-iron utilization pathway that includes an extracellular cascade of small secreted and GPI-anchored CFEM-type hemophores. These proteins can exchange heme captured from hemoglobin and other heme-binding proteins outside the cell. They form a heme transfer cascade that reaches across the cell wall to the plasma membrane, where the heme is internalized via an endocytic step to the vacuole. CFEM hemophores bind heme via a unique Asp-based heme iron coordination, which makes the interaction redox sensitive: only ferric heme (FeIII), and not the reduced ferrous heme (FeII), remains bound. To identify the predicted transmembrane heme receptor that connects the extracellular CFEM network with the endocytic pathway, we turned to phylogenetic profiling: taking advantage of the hundreds of fungal genomes available, we screened for genes jointly present across fungi with the CFEM heme transfer cascade genes. This enabled us to identify a new class of plasma membrane proteins, related to ferric reductases, that are essential for heme uptake. The hemoglobin-iron utilization pathway that emerges from these studies, which is distinct from bacterial systems, indicates that fungi have evolved a unique solution to the heme-iron acquisition problem. The presence of homologous CFEM hemophore cascade genes in many environmental fungi suggests that the ubiquitous heme molecule constitutes a common iron source for microorganisms.