Abstract
Aspergillus fumigatus is a primary and opportunistic pathogen, as well as a major allergen, of mammals. The Ca+2-calcineurin pathway affects virulence, morphogenesis and antifungal drug action in A. fumigatus. Here, we investigated three components of the A. fumigatus Ca+2-calcineurin pathway, pmcA,-B, and -C, which encode calcium transporters. We demonstrated that CrzA can directly control the mRNA accumulation of the pmcA-C genes by binding to their promoter regions. CrzA-binding experiments suggested that the 5′-CACAGCCAC-3′ and 5′-CCCTGCCCC-3′ sequences upstream of pmcA and pmcC genes, respectively, are possible calcineurin-dependent response elements (CDREs)-like consensus motifs. Null mutants were constructed for pmcA and -B and a conditional mutant for pmcC demonstrating pmcC is an essential gene. The ΔpmcA and ΔpmcB mutants were more sensitive to calcium and resistant to manganese and cyclosporin was able to modulate the sensitivity or resistance of these mutants to these salts, supporting the interaction between calcineurin and the function of these transporters. The pmcA-C genes have decreased mRNA abundance into the alveoli in the ΔcalA and ΔcrzA mutant strains. However, only the A. fumigatus ΔpmcA was avirulent in the murine model of invasive pulmonary aspergillosis.
Highlights
Calcium ions are extremely important for signal transduction
A phylogenetic analysis was performed in order to learn more about homologues of these transporters and other putative A. fumigatus calcium transporters (Figure 1)
We observed that the mRNA abundance of two PMC1 orthologous genes, pmcA (Afu1g10880) and pmcB (Afu3g10690), which encode calcium transporters, was dependent on CalA and CrzA (Soriani et al, 2008)
Summary
Two important calcium mediators in the eukaryotic cell are calmodulin and the phosphatase calcineurin [1,2]. Calcineurin plays an important role in the control of cell morphology and virulence [1,2,3,4]. The main mode of action of calcineurin is through the dephosphorylation of the transcription factor Crz1p [5]. Calcineurin dephosphorylates Crz1p upon an increase in cytosolic calcium, allowing its nuclear translocation [5,6]. CRZ1 deficient mutants display hypersensitivity to chloride and chitosan, a defective transcriptional response to alkaline stress and defects in cellular morphology and mating [5,7,8,9]. C. albicans homozygotes crz1D/D display moderately attenuated virulence and sensitive to calcium, lithium, manganese, and sodium dodecyl sulfate [6,11,12]
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