The FET4 gene encodes the low affinity Fe(II) transport protein of Saccharomyces cerevisiae

Dix, David; Bridgham, Jamie T.; Broderius, Margaret; Byersdorfer, Craig A.; Eide, David J.

doi:10.1016/s0021-9258(18)47163-3

Cited by 286 publications

(58 citation statements)

References 35 publications

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“…In a multicopy genomic library screen for suppressor genes of vps13 SDS hypersensitivity phenotype [43], we identified a plasmid containing the FET4 gene encoding a low affinity plasma membrane iron (Fe 2+ ) transporter [38] (Figure 5a). This finding indicated the importance of iron transport in the response to SDS stress.…”

Section: The Fet4 Gene Encoding Iron Transporter Fet4 Suppresses Vps13δ and Mutations Affecting Iron Transport Results In Sds Hypersensitmentioning

confidence: 99%

“…In iron-depleted conditions, yeast cells rely on high-affinity iron uptake systems consisting of Fet3 oxidase and Ftr1 permease. If iron is abundant, uptake is mediated by the low-affinity and low-specificity Fet4 transporter [38][39][40]. Another mechanism of iron uptake is the import of iron-siderophore chelates by siderophore transporters belonging to the Arn/Sit family of proteins [37].…”

Section: Introductionmentioning

confidence: 99%

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Flavonoids as Potential Drugs for VPS13-Dependent Rare Neurodegenerative Diseases

Soczewka

Flis

Tribouillard-Tanvier

et al. 2020

Genes

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Several rare neurodegenerative diseases, including chorea acanthocytosis, are caused by mutations in the VPS13A–D genes. Only symptomatic treatments for these diseases are available. Saccharomyces cerevisiae contains a unique VPS13 gene and the yeast vps13Δ mutant has been proven as a suitable model for drug tests. A library of drugs and an in-house library of natural compounds and their derivatives were screened for molecules preventing the growth defect of vps13Δ cells on medium with sodium dodecyl sulfate (SDS). Seven polyphenols, including the iron-binding flavone luteolin, were identified. The structure–activity relationship and molecular mechanisms underlying the action of luteolin were characterized. The FET4 gene, which encodes an iron transporter, was found to be a multicopy suppressor of vps13Δ, pointing out the importance of iron in response to SDS stress. The growth defect of vps13Δ in SDS-supplemented medium was also alleviated by the addition of iron salts. Suppression did not involve cell antioxidant responses, as chemical antioxidants were not active. Our findings support that luteolin and iron may target the same cellular process, possibly the synthesis of sphingolipids. Unveiling the mechanisms of action of chemical and genetic suppressors of vps13Δ may help to better understand VPS13A–D-dependent pathogenesis and to develop novel therapeutic strategies.

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Section: The Fet4 Gene Encoding Iron Transporter Fet4 Suppresses Vps13δ and Mutations Affecting Iron Transport Results In Sds Hypersensitmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Flavonoids as Potential Drugs for VPS13-Dependent Rare Neurodegenerative Diseases

Soczewka

Flis

Tribouillard-Tanvier

et al. 2020

Genes

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“…We also described flavonoids as a group of compounds which mitigate vps13∆ growth defect [57]. Finally, we showed that the FET4 gene, encoding a low-affinity and low-specificity iron transporter [58][59][60], is a multicopy suppressor of vps13∆, and that iron is important for yeast growth in the presence of SDS [57].…”

Section: Introductionmentioning

confidence: 88%

Targeting Copper Homeostasis Improves Functioning of vps13Δ Yeast Mutant Cells, a Model of VPS13-Related Diseases

Soczewka

Tribouillard-Tanvier

Rago

et al. 2021

IJMS

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Ion homeostasis is crucial for organism functioning, and its alterations may cause diseases. For example, copper insufficiency and overload are associated with Menkes and Wilson’s diseases, respectively, and iron imbalance is observed in Parkinson’s and Alzheimer’s diseases. To better understand human diseases, Saccharomyces cerevisiae yeast are used as a model organism. In our studies, we used the vps13Δ yeast strain as a model of rare neurological diseases caused by mutations in VPS13A-D genes. In this work, we show that overexpression of genes encoding copper transporters, CTR1, CTR3, and CCC2, or the addition of copper salt to the medium, improved functioning of the vps13Δ mutant. We show that their mechanism of action, at least partially, depends on increasing iron content in the cells by the copper-dependent iron uptake system. Finally, we present that treatment with copper ionophores, disulfiram, elesclomol, and sodium pyrithione, also resulted in alleviation of the defects observed in vps13Δ cells. Our study points at copper and iron homeostasis as a potential therapeutic target for further investigation in higher eukaryotic models of VPS13-related diseases.

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“…Since then, both metallo-reductases have also been found to reduce both cupric and ferric ions, where FRE1 expression induces the reduction of Cu 2+ when transcription factor Mac1 is bound, and Fe 3+ reduction occurs via binding of transcription factor Aft1 [176,181,225]. After Fe 3+ reduction, Fe 2+ is then ready for uptake by a six domain, transmembrane, metal transporter, Fet4 [54,55]. Fet4 can also import other metals, but is mostly responsible for Fe 2+ uptake in iron-restricted cells [223].…”

Section: Iron Transport and Homeostasismentioning

confidence: 99%

Fungal–Metal Interactions: A Review of Toxicity and Homeostasis

Robinson

Isikhuemhen

Anike

2021

JoF

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Metal nanoparticles used as antifungals have increased the occurrence of fungal–metal interactions. However, there is a lack of knowledge about how these interactions cause genomic and physiological changes, which can produce fungal superbugs. Despite interest in these interactions, there is limited understanding of resistance mechanisms in most fungi studied until now. We highlight the current knowledge of fungal homeostasis of zinc, copper, iron, manganese, and silver to comprehensively examine associated mechanisms of resistance. Such mechanisms have been widely studied in Saccharomyces cerevisiae, but limited reports exist in filamentous fungi, though they are frequently the subject of nanoparticle biosynthesis and targets of antifungal metals. In most cases, microarray analyses uncovered resistance mechanisms as a response to metal exposure. In yeast, metal resistance is mainly due to the down-regulation of metal ion importers, utilization of metallothionein and metallothionein-like structures, and ion sequestration to the vacuole. In contrast, metal resistance in filamentous fungi heavily relies upon cellular ion export. However, there are instances of resistance that utilized vacuole sequestration, ion metallothionein, and chelator binding, deleting a metal ion importer, and ion storage in hyphal cell walls. In general, resistance to zinc, copper, iron, and manganese is extensively reported in yeast and partially known in filamentous fungi; and silver resistance lacks comprehensive understanding in both.

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The FET4 gene encodes the low affinity Fe(II) transport protein of Saccharomyces cerevisiae

Cited by 286 publications

References 35 publications

Flavonoids as Potential Drugs for VPS13-Dependent Rare Neurodegenerative Diseases

Flavonoids as Potential Drugs for VPS13-Dependent Rare Neurodegenerative Diseases

Targeting Copper Homeostasis Improves Functioning of vps13Δ Yeast Mutant Cells, a Model of VPS13-Related Diseases

Fungal–Metal Interactions: A Review of Toxicity and Homeostasis

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