A copper transcription factor, AfMac1, regulates both iron and copper homeostasis in the opportunistic fungal pathogen <i>Aspergillus fumigatus</i>

Park, Yong Sung; Kang, Suzie; Seo, Hyewon; Yun, Cheol Won

doi:10.1042/bcj20180399

Cited by 18 publications

(17 citation statements)

References 51 publications

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“…1). It has recently been reported that AfMacA also regulates iron homeostasis and its localization in the cell varies depending on copper and iron concentration (Park et al 2018). AfmacA disruption generated a copper starvation phenotype with manifest growth defects in copper depletion conditions (Cai et al 2017;Kusuya et al 2017;Park et al 2017).…”

Section: Genetic Regulation Of Copper Homeostasismentioning

confidence: 99%

New insights into copper homeostasis in filamentous fungi

Antsotegi-Uskola

Markina-Iñarrairaegui

Ugalde

2019

Int Microbiol

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Copper is a metal ion that is required as a micronutrient for growth and proliferation. However, copper accumulation generates toxicity by multiple mechanisms, potentially leading to cell death. Due to its toxic nature at high concentrations, different chemical variants of copper have been extensively used as antifungal agents in agriculture and medicine. Most studies on copper homeostasis have been carried out in bacteria, yeast, and mammalian organisms. However, knowledge on filamentous fungi is less well documented. This review summarizes the knowledge gathered in the last few years about copper homeostasis in the filamentous fungi Aspergillus fumigatus and Aspergillus nidulans: The mechanism of action of copper, the uptake and detoxification systems, their regulation at the transcriptional level, and the role of copper homeostasis in fungal pathogenicity are presented.

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Section: Genetic Regulation Of Copper Homeostasismentioning

confidence: 99%

New insights into copper homeostasis in filamentous fungi

Antsotegi-Uskola

Markina-Iñarrairaegui

Ugalde

2019

Int Microbiol

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“…Zinc is an essential trace element and performs various physiological functions in living cells. Previously, we found that copper regulates iron metabolism [ 40 ], and in this report, we sought to understand the interaction between zinc and copper metabolism. To investigate the effect of zinc on copper metabolism in A. fumigatus , the effect of zinc on growth of the Δafmac1 strain was investigated.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, we reported that iron and copper interact functionally in A. fumigatus and that copper regulates iron metabolism, and vice versa [ 40 , 41 ]. We observed that iron regulates the expression of genes related to copper metabolism, and another group reported that iron and zinc functionally interact with one another.…”

Section: Introductionmentioning

confidence: 99%

“…We observed that iron regulates the expression of genes related to copper metabolism, and another group reported that iron and zinc functionally interact with one another. For example, we reported that the copper-responsive transcription factor AfMac1 regulates the expression of genes involved in the reductive and siderophore-mediated iron uptake system [ 40 ]. This report indicates that metals interact with each other in cells to regulate homeostasis of other metals, and this regulation is mutual.…”

Section: Introductionmentioning

confidence: 99%

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The Role of Zinc in Copper Homeostasis of Aspergillus fumigatus

Kang

Seo

Moon

et al. 2020

IJMS

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Copper is an essential metal ion that performs many physiological functions in living organisms. Deletion of Afmac1, which is a copper-responsive transcriptional activator in A. fumigatus, results in a growth defect on aspergillus minimal medium (AMM). Interestingly, we found that zinc starvation suppressed the growth defect of the Δafmac1 strain on AMM. In addition, the growth defect of the Δafmac1 strain was recovered by copper supplementation or introduction of the CtrC gene into the Δafmac1 strain. However, chelation of copper by addition of BCS to AMM failed to recover the growth defect of the Δafmac1 strain. Through Northern blot analysis, we found that zinc starvation upregulated CtrC and CtrA2, 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 CtrC and CtrA2 and that mutation of the binding motif led to failure of ZafA binding to the upstream region of CtrC and upregulation of CtrC expression under zinc starvation. Furthermore, the binding activity of ZafA to the upstream region of CtrC was inversely proportional to the zinc concentration, and copper inhibited the binding of ZafA to the upstream region of CtrC under a low zinc concentration. Taken together, these results suggest that ZafA upregulates copper metabolism by binding to the ZafA binding motif in the CtrC promoter region under low zinc concentration, thus regulating copper homeostasis. Furthermore, we found that copper and zinc interact in cells to maintain metal homeostasis.

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“…Copper has historically been used to control fungal and bacterial growth in healthcare settings (Casey et al., 2010; Lazary et al., 2014). It has become apparent that hosts use copper to fight A. fumigatus infection, and A. fumigatus has also evolved some mechanisms to resist copper-mediated toxicity by regulating copper homeostasis (Kusuya et al., 2017; Wiemann et al., 2017; Cai et al., 2018; Park et al., 2018). Thus, copper plays an important role at the host– A. fumigatus axis, and a detailed understanding of copper homeostasis regulation in A. fumigatus can lead to new strategies for antifungal drug development.…”

Section: Introductionmentioning

confidence: 99%

Copper Homeostasis in Aspergillus fumigatus: Opportunities for Therapeutic Development

Song

Jiang

2019

Front. Microbiol.

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Aspergillus fumigatus can cause severe invasive aspergillosis in immunocompromised individuals. Copper, an essential but potentially toxic trace element for A. fumigatus , plays a critical role at the host-pathogen axis during infection. Accumulating evidence demonstrates that the host utilizes copper compartmentalization within macrophages to combat A. fumigatus infection. To survive under host-imposed copper toxicity, A. fumigatus has evolved sophisticated machinery to regulate copper homeostasis. Thus, targeting molecular pathways critical for copper homeostasis regulation provides an opportunity to improve therapeutic options for aspergillosis caused by A. fumigatus . In this review, we describe the copper homeostatic mechanisms by which A. fumigatus acquires and controls copper levels and explores the responses of the pathogen to alter copper levels in the host. Finally, we discuss the regulatory mechanisms of copper homeostasis that could be targeted for antifungal drug development.

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A copper transcription factor, AfMac1, regulates both iron and copper homeostasis in the opportunistic fungal pathogen Aspergillus fumigatus

Cited by 18 publications

References 51 publications

New insights into copper homeostasis in filamentous fungi

New insights into copper homeostasis in filamentous fungi

The Role of Zinc in Copper Homeostasis of Aspergillus fumigatus

Copper Homeostasis in Aspergillus fumigatus: Opportunities for Therapeutic Development

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