Metabolic remodeling in iron-deficient fungi

Philpott, Caroline C.; Leidgens, Sébastien; Frey, Avery G.

doi:10.1016/j.bbamcr.2012.01.012

Cited by 98 publications

(108 citation statements)

References 100 publications

(151 reference statements)

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“…As a redox-active metal, iron is an important cofactor in a variety of enzymes that are intimately linked to essential cellular functions such as DNA synthesis, oxidative phosphorylation, and the biosynthesis of metabolites (10,36). Ironically, this same redox property allows iron to undergo Fenton-type chemical reactions that result in the production of hydroxyl radicals that can lead to cell death (8).…”

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confidence: 99%

The Monothiol Glutaredoxin Grx4 Exerts an Iron-Dependent Inhibitory Effect on Php4 Function

et al. 2012

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When iron is scarce, Schizosaccharomyces pombe cells repress transcription of several genes that encode iron-using proteins. Php4 mediates this transcriptional control by specifically interacting with the CCAAT-binding core complex that is composed of Php2, Php3, and Php5. In contrast, when there is sufficient iron, Php4 is inactivated, thus allowing the transcription of many genes that encode iron-requiring proteins. Analysis by bimolecular fluorescence complementation and two-hybrid assays showed that Php4 and the monothiol glutaredoxin Grx4 physically interact with each other. Deletion mapping analysis revealed that the glutaredoxin (GRX) domain of Grx4 associates with Php4 in an iron-dependent manner. Site-directed mutagenesis identified the Cys172 of Grx4 as being required for this iron-dependent association. Subsequent analysis showed that, although the thioredoxin (TRX) domain of Grx4 interacts strongly with Php4, this interaction is insensitive to iron. Fine mapping analysis revealed that the Cys35 of Grx4 is necessary for the association between the TRX domain and Php4. Taken together, the results revealed that whereas the TRX domain interacts constitutively with Php4, the GRX domain-Php4 association is both modulated by iron and required for the inhibition of Php4 activity in response to iron repletion.

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The Monothiol Glutaredoxin Grx4 Exerts an Iron-Dependent Inhibitory Effect on Php4 Function

et al. 2012

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“…Studies on nonphotosynthetic unicellular organisms such as bacteria and yeast have suggested that programs exist to acclimate metabolism to Fe deficiency (Oglesby-Sherrousse and Murphy, 2013;Philpott et al, 2012). Compared to heterotrophs, photosynthetic organisms have to cope with a substantially higher demand for Fe because of the added Fe requirement of the chloroplast (for review, see BlabyHaas and Merchant, 2013).…”

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A Program for Iron Economy during Deficiency Targets Specific Fe Proteins

et al. 2017

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“…Aft1 and Aft2 play a central role in iron-dependent transcription activation of genes encoding components involved in cellular uptake and intracellular distribution of iron (9,10). Yap5 is involved in the detoxification of excess iron by inducing the transcription of, e.g., CCC1 encoding the only known iron importer into the vacuole, the major metal storage organelle in fungi (11,12).…”

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The Basic Leucine Zipper Stress Response Regulator Yap5 Senses High-Iron Conditions by Coordination of [2Fe-2S] Clusters

Rietzschel

Pierik

Bill

et al. 2015

Molecular and Cellular Biology

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Iron is an essential, yet at elevated concentrations toxic trace element. To date, the mechanisms of iron sensing by eukaryotic iron-responsive transcription factors are poorly understood. The Saccharomyces cerevisiae transcription factor Yap5, a member of the Yap family of bZIP stress response regulators, administrates the adaptive response to high-iron conditions. Despite the central role of the iron-sensing process for cell viability, the molecule perceived by Yap5 and the underlying regulatory mechanisms are unknown. Here, we show that Yap5 senses high-iron conditions by two Fe/S clusters bound to its activator domain (Yap5-AD). The more stable iron-regulatory Fe/S cluster at the N-terminal cysteine-rich domain (n-CRD) of Yap5 is detected in vivo and in vitro. Iron is a key trace element for virtually all organisms. It functions as an essential cofactor in electron transfer, metabolite biosynthesis, DNA metabolism, and protein translation. Although iron is highly abundant, its bioavailability is low due to its poor solubility under ambient conditions (1, 2). For microbial pathogens, iron acquisition from their host cells is frequently crucial for their virulence. Hence, mutations in microbial genes involved in iron acquisition or utilization are associated with the loss of pathogenicity (3, 4). On the other hand, high intracellular iron levels are both a source and an amplifier of reactive oxygen species and thus highly toxic.Iron acquisition, transport and storage need to be tightly regulated, and disruption or deregulation of iron-related molecules can have significant health consequences. Hence, organisms have developed sophisticated and largely divergent strategies to acquire appropriate cellular iron levels and to avoid iron overloading (5-7). Except for vertebrates, which regulate cellular iron homeostasis mainly on the level of translation by the iron-regulatory proteins IRP1 and IRP2, transcriptional control of iron-responsive gene expression is widespread (7). In a large number of fungi, iron-responsive gene expression is conferred by the interplay of two conserved transcriptional repressors. Of these, the GATAtype transcription factor SreA regulates the expression of genes involved in iron uptake, while the basic leucine zipper (bZIP) transcription factor HapX regulates the iron-responsive expression of genes involved in iron-consuming pathways through interaction with the CCAAT-binding complex CBC (4,8).The model organism Saccharomyces cerevisiae utilizes three iron-responsive transcription factors. Aft1 and Aft2 play a central role in iron-dependent transcription activation of genes encoding components involved in cellular uptake and intracellular distribution of iron (9, 10). Yap5 is involved in the detoxification of excess iron by inducing the transcription of, e.g., CCC1 encoding the only known iron importer into the vacuole, the major metal storage organelle in fungi (11,12). Yap5 belongs to a fungus-specific family of stress response regulators that contains eight members in S. cerevisiae (...

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Metabolic remodeling in iron-deficient fungi

Cited by 98 publications

References 100 publications

The Monothiol Glutaredoxin Grx4 Exerts an Iron-Dependent Inhibitory Effect on Php4 Function

The Monothiol Glutaredoxin Grx4 Exerts an Iron-Dependent Inhibitory Effect on Php4 Function

A Program for Iron Economy during Deficiency Targets Specific Fe Proteins

The Basic Leucine Zipper Stress Response Regulator Yap5 Senses High-Iron Conditions by Coordination of [2Fe-2S] Clusters

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