The ErpA/NfuA complex builds an oxidation-resistant Fe-S cluster delivery pathway

Py, Béatrice; Gerez, Catherine; Huguenot, Allison; Vidaud, Claude; Fontecave, Marc; Choudens, Sandrine Ollagnier de; Barras, Frédéric

doi:10.1074/jbc.ra118.002160

Cited by 35 publications

(30 citation statements)

References 56 publications

(79 reference statements)

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“…NfuA and ErpA are additional Fe-S carriers that can cooperate under oxidative stress conditions [ 37 – 39 ]. Moreover, they are able to receive Fe-S clusters made within either ISC or SUF systems [ 37 – 39 ]. Given that SoxR is a stress responding regulator, it was of interest to evaluate the role of ErpA and NfuA in SoxR maturation.…”

Section: Resultsmentioning

confidence: 99%

Oxidative stress antagonizes fluoroquinolone drug sensitivity via the SoxR-SUF Fe-S cluster homeostatic axis

Gerstel

Beas²,

Duverger³

et al. 2020

PLoS Genet

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The level of antibiotic resistance exhibited by bacteria can vary as a function of environmental conditions. Here, we report that phenazine-methosulfate (PMS), a redox-cycling compound (RCC) enhances resistance to fluoroquinolone (FQ) norfloxacin. Genetic analysis showed that E . coli adapts to PMS stress by making Fe-S clusters with the SUF machinery instead of the ISC one. Based upon phenotypic analysis of soxR , acrA , and micF mutants, we showed that PMS antagonizes fluoroquinolone toxicity by SoxR-mediated up-regulation of the AcrAB drug efflux pump. Subsequently, we showed that despite the fact that SoxR could receive its cluster from either ISC or SUF, only SUF is able to sustain efficient SoxR maturation under exposure to prolonged PMS period or high PMS concentrations. This study furthers the idea that Fe-S cluster homeostasis acts as a sensor of environmental conditions, and because its broad influence on cell metabolism, modifies the antibiotic resistance profile of E . coli .

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Section: Resultsmentioning

confidence: 99%

Oxidative stress antagonizes fluoroquinolone drug sensitivity via the SoxR-SUF Fe-S cluster homeostatic axis

Gerstel

Beas²,

Duverger³

et al. 2020

PLoS Genet

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“…More recently, it has been proposed in E . coli that NfuA assists ErpA in delivery of [Fe-S] cluster to the target proteins under unfavorable conditions such as oxidative stress [ 35 ]. High expression of erpA could complement the paraquat-sensitive phenotype of E .…”

Section: Resultsmentioning

confidence: 99%

“…High expression of erpA could complement the paraquat-sensitive phenotype of E . coli nfuA mutant [ 35 ]. Nevertheless, expression of a PAO1 erpA -homolog from pErpA pa failed to restore the paraquat-sensitive phenotype of the Δ nfuA mutant (data not shown).…”

Section: Resultsmentioning

confidence: 99%

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Pseudomonas aeruginosa nfuA: Gene regulation and its physiological roles in sustaining growth under stress and anaerobic conditions and maintaining bacterial virulence

et al. 2018

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The role of the nfuA gene encoding an iron-sulfur ([Fe-S]) cluster-delivery protein in the pathogenic bacterium Pseudomonas aeruginosa was investigated. The analysis of nfuA expression under various stress conditions showed that superoxide generators, a thiol-depleting agent and CuCl2 highly induced nfuA expression. The expression of nfuA was regulated by a global [2Fe-2S] cluster containing the transcription regulator IscR. Increased expression of nfuA in the ΔiscR mutant under uninduced conditions suggests that IscR acts as a transcriptional repressor. In vitro experiments revealed that IscR directly bound to a sequence homologous to the Escherichia coli Type-I IscR-binding motifs on a putative nfuA promoter that overlapped the -35 element. Binding of IscR prevented RNA polymerase from binding to the nfuA promoter, leading to repression of the nfuA transcription. Physiologically, deletion of nfuA reduced the bacterial ability to cope with oxidative stress, iron deprivation conditions and attenuated virulence in the Caenorhabditis elegans infection model. Site-directed mutagenesis analysis revealed that the conserved CXXC motif of the Nfu-type scaffold protein domain at the N-terminus was required for the NfuA functions in conferring the stress resistance phenotype. Furthermore, anaerobic growth of the ΔnfuA mutant in the presence of nitrate was drastically retarded. This phenotype was associated with a reduction in the [Fe-S] cluster containing nitrate reductase enzyme activity. However, NfuA was not required for the maturation of [Fe-S]-containing proteins such as aconitase, succinate dehydrogenase, SoxR and IscR. Taken together, our results indicate that NfuA functions in [Fe-S] cluster delivery to selected target proteins that link to many physiological processes such as anaerobic growth, bacterial virulence and stress responses in P. aeruginosa.

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“…The basic features of the LYR motif include an aliphatic residue, followed by a large aromatic (tyrosine or phenylalanine), followed by a positively charged arginine or lysine, which can be modeled to fit into a pocket of the solved structure of HSC20 (Maio and Rouault 2016 ; Bitto et al 2008 ). Thus, the basic apparatus of the Fe–S biogenesis machinery has been defined for mitochondrial Fe–S biogenesis, though the roles of other involved proteins such as glutaredoxin 5 (GLRX5) (Ye et al 2010 ), ISCA, a putative scaffold protein (Py et al 2018 ) and multiple other proteins such as NFU (Tong et al 2003 ) have not been specifically assigned, and may be involved as secondary scaffold carriers that deliver clusters to a subset of Fe–S proteins.…”

Section: Dissecting the Mechanism Of Fe–s Delivery To Recipient Protementioning

confidence: 99%

The indispensable role of mammalian iron sulfur proteins in function and regulation of multiple diverse metabolic pathways

Rouault

2019

Biometals

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In recent years, iron sulfur (Fe–S) proteins have been identified as key players in mammalian metabolism, ranging from long-known roles in the respiratory complexes and the citric acid cycle, to more recently recognized roles in RNA and DNA metabolism. Fe–S cofactors have often been missed because of their intrinsic lability and oxygen sensitivity. More Fe–S proteins have now been identified owing to detection of their direct interactions with components of the Fe–S biogenesis machinery, and through use of informatics to detect a motif that binds the co-chaperone responsible for transferring nascent Fe–S clusters to domains of recipient proteins. Dissection of the molecular steps involved in Fe–S transfer to Fe–S proteins has revealed that direct and shielded transfer occurs through highly conserved pathways that operate in parallel in the mitochondrial matrix and in the cytosolic/nuclear compartments of eukaryotic cells. Because Fe–S clusters have the unusual ability to accept or donate single electrons in chemical reactions, their presence renders complex chemical reactions possible. In addition, Fe–S clusters may function as sensors that interconnect activity of metabolic pathways with cellular redox status. Presence in pathways that control growth and division may enable cells to regulate their growth according to sufficiency of energy stores represented by redox capacity, and oxidation of such proteins could diminish anabolic activities to give cells an opportunity to restore energy supplies. This review will discuss mechanisms of Fe–S biogenesis and delivery, and methods that will likely reveal important roles of Fe–S proteins in proteins not yet recognized as Fe–S proteins.

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The ErpA/NfuA complex builds an oxidation-resistant Fe-S cluster delivery pathway

Cited by 35 publications

References 56 publications

Oxidative stress antagonizes fluoroquinolone drug sensitivity via the SoxR-SUF Fe-S cluster homeostatic axis

Oxidative stress antagonizes fluoroquinolone drug sensitivity via the SoxR-SUF Fe-S cluster homeostatic axis

Pseudomonas aeruginosa nfuA: Gene regulation and its physiological roles in sustaining growth under stress and anaerobic conditions and maintaining bacterial virulence

The indispensable role of mammalian iron sulfur proteins in function and regulation of multiple diverse metabolic pathways

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