The Role of Zinc in Copper Homeostasis of Aspergillus fumigatus

Copper is an essential metal ion that performs many physiological functions in living organisms. Deletion of which is a copper-responsive transcriptional activator in , results in a growth defect on aspergillus minimal medium (AMM). Interestingly, we found that zinc starvation suppressed the growth defect of the strain on AMM. In addition, the growth defect of the strain was recovered by copper supplementation or introduction of the gene into the strain. However, chelation of copper by addition of BCS to AMM failed to recover the growth defect of the strain. Through Northern blot analysis, we found that zinc starvation upregulated and , which encode membrane copper transporters. Interestingly, we found that the conserved ZafA binding motif 5'-CAA(G)GGT-3' was present in the upstream region of and and that mutation of the binding motif led to failure of ZafA binding to the upstream region of and upregulation of expression under zinc starvation. Furthermore, the binding activity of ZafA to the upstream region of was inversely proportional to the zinc concentration, and copper inhibited the binding of ZafA to the upstream region of under a low zinc concentration. Taken together, these results suggest that ZafA upregulates copper metabolism by binding to the ZafA binding motif in the promoter region under low zinc concentration, thus regulating copper homeostasis. Furthermore, we found that copper and zinc interact in cells to maintain metal homeostasis.