Ferric Reductases in Candida albicans: Expression and Regulation

Candida albicans is an opportunistic fungal pathogen of humans causing superficial mucosal infections and more serious systemic infections in immunocompromised individuals. It is found in both yeast and hyphal forms at sites of infection. In the human body levels of iron are extremely low, and an invading organism needs a way of sequestering iron. In C. albicans there is a high affinity iron uptake system in which iron is first reduced to the soluble ferrous form by ferric reductases. Reduced iron is then taken up into the cell by a complex of a multicopper oxidase protein with an iron transport protein. Multicopper oxidase proteins require copper to function and so high affinity iron and copper uptake is inextricably linked. It has previously been demonstrated that CaFre10p is the major cell surface ferric and cupric reductase. It is shown here that CaFre7p also makes a significant contribution to cell surface ferric and cupric reductase activity. However, whereas CaFRE10 is regulated in response to iron levels, CaFRE7 is regulated in a copper responsive manner. The CaFRE10 gene is regulated by the GATA-type transcriptional repressor Sfu1p and CaFRE7 is not. We show that in a mutant containing a deletion of SFU1 the expression of the major iron transport protein CaFTR1 is increased and there is a corresponding increase in radioactive iron uptake. It is also shown here for the first time that expression of CaFRE10 and CaFRE7 is lower in hyphae compared to yeast and that this leads to a corresponding decrease in cell surface ferric, but not cupric reductase activity. This shows for the first time that two important virulence determinants, the acquisition of iron and the morphological form of C. albicans, are linked.