Candida albicans, a normally harmless commensal organism, can cause life-threatening systemic infections among immunocompromised patients. The human host invests substantial efforts into withdrawing iron from potential pathogens. To overcome the extreme iron limitation in the host, C. albicans, similar to many pathogenic bacteria, has evolved several mechanisms, including a pathway for heme-iron scavenging that enables access to hemoglobin, the largest iron pool in the human body. Genetic and biochemical analysis identified a series of extracellular GPI-anchored and secreted proteins of the CFEM family that extract heme from hemoglobin and transfer it from one protein to the next across the cell wall. Furthermore, utilization of heme-iron was found to require endocytosis via the ESCRT pathway. However the transmembrane protein mediating this endocytosis step remained unidentified. Here we identify a candidate heme-transporting membrane protein. Ferric reductases are heme proteins located on the plasma membrane. C. albicans carries about 17 ferric reductase-encoding genes. Two divergent members of this family were found by phylogenetic footprinting to segregate across Ascomycota together with the heme-binding CFEM proteins. Deletion of one of these two genes resulted in a strong reduction in the ability to utilize hemoglobin-iron, supporting a possible function for this protein as a transmembrane heme receptor.
