Abstract
Zinc performs diverse physiological functions, and virtually all living organisms require zinc as an essential trace element. To identify the detailed function of zinc in fungal pathogenicity, we carried out cDNA microarray analysis using the model system of Aspergillus fumigatus, a fungal pathogen. From microarray analysis, we found that the genes involved in gliotoxin biosynthesis were upregulated when zinc was depleted, and the microarray data were confirmed by northern blot analysis. In particular, zinc deficiency upregulated the expression of GliZ, which encodes a Zn2-Cys6 binuclear transcription factor that regulates the expression of the genes required for gliotoxin biosynthesis. The production of gliotoxin was decreased in a manner inversely proportional to the zinc concentration, and the same result was investigated in the absence of ZafA, which is a zinc-dependent transcription activator. Interestingly, we found two conserved ZafA-binding motifs, 5′-CAAGGT-3′, in the upstream region of GliZ on the genome and discovered that deletion of the ZafA-binding motifs resulted in loss of ZafA-binding activity; gliotoxin production was decreased dramatically, as demonstrated with a GliZ deletion mutant. Furthermore, mutation of the ZafA-binding motifs resulted in an increase in the conidial killing activity of human macrophage and neutrophil cells, and virulence was decreased in a murine model. Finally, transcriptomic analysis revealed that the expression of ZafA and GliZ was upregulated during phagocytosis by macrophages. Taken together, these results suggest that zinc plays an important role in the pathogenicity of A. fumigatus by regulating gliotoxin production during the phagocytosis pathway to overcome the host defense system.
Highlights
Iron, copper, and zinc are representative essential trace elements and perform many physiological roles in living organisms
We found that many genes involved in cellular metabolism were down- or upregulated by zinc
We found that the genes involved in gliotoxin biosynthesis were upregulated under zinc-deficient conditions
Summary
Copper, and zinc are representative essential trace elements and perform many physiological roles in living organisms. Iron is an essential metal ion that works as a cofactor of many enzymes, and iron deficiency results in fatal diseases, such as hereditary anemia [1]. Iron overload induces the so-called Fenton reaction, which mediates the production of hydroxyl radicals and is fatal to living cells by affecting DNA and proteins [2]. For this reason, iron homeostasis is strictly regulated. Copper carries out many important roles in living organisms, and copper deficiency or overload causes severe genetic diseases, such as Menkes disease or Wilson disease [3], respectively. Copper, and zinc are divalent metal ions that carry out oxidoreduction reactions and produce reactive oxygen species that affect cellular activity
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