Deletion of the copper transporter CaCCC2 reveals two distinct pathways for iron acquisition in Candida albicans.
Efficient iron acquisition is an essential requirement for growth of pathogenic organisms in the iron-poor host environment. In Saccharomyces cerevisiae, high-affinity iron import depends on the multicopper ferroxidase ScFet3. ScFet3 biogenesis in the trans-Golgi compartment requires a copper-transporting P-type ATPase, ScCcc2. Here, we describe the isolation by functional complementation of a Ccc2 homologue from the pathogenic yeast Candida albicans. CaCcc2 is functionally distinct from a previously described C. albicans copper-transporting P-type ATPase, CaCrp1, which appears to be specifically involved in copper detoxification. Regulation of CaCCC2 and the phenotype of the homozygous CaCCC2 deletion indicate that it is required for high-affinity iron import, making it the bona fide CCC2 homologue of C. albicans. Remarkably, in a mouse model of systemic infection, the Caccc2Delta strain displayed robust proliferation and no significant reduction in pathogenicity, suggesting the existence of alternative mechanisms of iron uptake from host tissues. We identify haemin and haemoglobin as potential iron sources that can be used by C. albicans in a CaCcc2-independent manner.
Weissman
Ziva
Z
Department of Molecular Microbiology, Technion-B. Rappaport Faculty of Medicine, Haifa 31096, Israel.
Shemer
Revital
R
Kornitzer
Daniel
D
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002176:Candida albicans / Q000201:enzymology / Q000378:metabolism* / Q000472:pathogenicity; D027682:Cation Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003300:Copper / Q000378:metabolism*; D000079922:Copper Transport Proteins; D004195:Disease Models, Animal; D017353:Gene Deletion; D015966:Gene Expression Regulation, Fungal; D005816:Genetic Complementation Test; D007501:Iron / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010641:Phenotype; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
C092974:CCC2 protein, S cerevisiae; D027682:Cation Transport Proteins; D000079922:Copper Transport Proteins; D026901:Membrane Transport Proteins; D029701:Saccharomyces cerevisiae Proteins; D003300:Copper; D007501:Iron; D000251:Adenosine Triphosphatases