Abstract
Most of the metal transporters in Aspergillus fumigatus are yet uncharacterized. Their role in fungal metabolism and virulence remains unclear. This paper describes the novel PIB-type cation ATPase PcaA, which links metal homeostasis and heavy metal tolerance in the opportunistic human pathogen A. fumigatus. The protein possesses conserved ATPase motif and shares 51% amino acid sequence identity with the Saccharomyces cerevisiae cadmium exporter Pca1p. A pcaA deletion, an overexpression and a gfp-pcaA complementation strain of A. fumigatus were constructed and their heavy metal susceptibilities were studied. The pcaA knock out strain showed drastically decreased cadmium tolerance, however, its growth was not affected by the exposure to high concentrations of copper, iron, zinc, or silver ions. Although the lack of PcaA had no effect on copper adaption, we demonstrated that not only cadmium but also copper ions are able to induce the transcription of pcaA in A. fumigatus wild type Af293. Similarly, cadmium and copper ions could induce the copper exporting ATPase crpA. These data imply a general response on the transcriptomic level to heavy metals in A. fumigatus through the induction of detoxification systems. Confocal microscopy of the gfp-pcaA complementation strain expressing functional GFP-PcaA supports the predicted membrane localization of PcaA. The GFP-PcaA fusion protein is located in the plasma membrane of A. fumigatus in the presence of cadmium ions. Virulence assays support a function of PcaA for virulence of A. fumigatus in the Galleria mellonella wax moth larvae model, which might be linked to the elimination of reactive oxygen species.
Highlights
Aspergillus fumigatus is a competitive saprophytic mold widespread in nature, mostly found in soil and on decaying organic matter
In our work we focused on describing Pca1p-type proteins which confer cadmium tolerance to A. fumigatus
Sequence homology modeling of PcaA executed by Phyre2 (Kelley et al, 2015) discovered eight membrane spanning helices which are typical for PIB-type ATPases (Kühlbrandt, 2004) (Figure 1B)
Summary
Aspergillus fumigatus is a competitive saprophytic mold widespread in nature, mostly found in soil and on decaying organic matter. As a saprophyte as well as a pathogen, A. fumigatus has the ability for rapid adaptation to changing environmental conditions, may it be heavy metal pollution or oxidative stress exerted by the host cell as part of its defense mechanism (Aguirre et al, 2006) This ability manifests in a wide tolerance of this fungus for unfavorable conditions such as heat (Jesenská et al, 1993; Bhabhra and Askew, 2005), heavy metal (Fazli et al, 2015), oxidative stress (Qiao et al, 2008; Muszkieta et al, 2014) or resistance against antifungal agents (Wiederhold and Patterson, 2015; Brown and Goldman, 2016). Cells of the innate immune response, the macrophages use copper ions to eliminate pathogens (Festa and Thiele, 2011; Stafford et al, 2013; Ding et al, 2014; Djoko et al, 2015)
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