Novel insight into the expression and function of the multicopper oxidases in Candida albicans

Iron is an essential element required for most organisms. The high-affinity iron-uptake systems in the opportunistic pathogen Candida albicans are activated under iron-limited conditions and are also required for virulence. Here one component of high-affinity iron-uptake systems, the multicopper oxidase (MCO) genes, was characterized. We examined the expression of five MCO genes and demonstrated that CaFET3 and CaFET34 were the major MCO genes in response to iron deficiency. Complementation of the Saccharomyces cerevisiae fet3Δ mutant showed that CaFET34 could effectively rescue the growth phenotype in iron-limited medium. Deletion of CaFET33 and CaFET34 in C. albicans decreased cellular iron content and iron acquisition during iron starvation. However, the fet33Δ/Δ and fet34Δ/Δ mutants exhibited no obvious growth defect in solid iron-limited medium while the fet34Δ/Δ mutant showed a slight growth defect in liquid medium. Further analysis shows that other members of the five MCO genes, especially CaFET3, would compensate for the absence of CaFET33 and CaFET34. Furthermore, for the first time, we provide evidence that CaFET34 is implicated in hyphal development in an iron-independent manner and is required for C. albicans virulence in a mouse model of systemic infection. Together, our results not only expand our understanding about the expression of the MCO genes in C. albicans, but also provide a novel insight into the role of CaFET34 in iron metabolism, hyphal development and virulence.