IdeR in Mycobacteria: From Target Recognition to Physiological Function

Ranjan, Sarita; Yellaboina, Sailu; Ranjan, Akash

doi:10.1080/10408410600709768

Cited by 15 publications

(11 citation statements)

References 59 publications

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“…Manganese-responsive DtxR family regulators were studied in many bacteria, including MntR in Escherichia coli (11), Bacillus subtilis (12), Staphylococcus aureus (13), Corynebacterium diphtheria (14), and C. glutamicum (15,16), ScaR in Streptococcus gordonii (17), and TroR in Treponema pallidum (18), where they mostly control genes for manganese uptake transporters. In contrast, iron-responsive TFs from the DtxR family were found only in Actinobacteria and include two experimentally studied TFs, the diphtheria toxin repressor DtxR in Corynebacterium diphtheriae (19) and the iron-dependent regulator IdeR in Mycobacterium tuberculosis (20,21), which control large networks of genes involved in iron homeostasis and other cellular functions, such as the toxin gene in C. diphtheriae. The natural ligand for IdeR/DtxR is ferrous iron, but divalent ions of nickel, cobalt, manganese, and zinc also bind to and activate the regulators in vitro (22).…”

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confidence: 99%

Comparative Genomics of DtxR Family Regulons for Metal Homeostasis in Archaea

Leyn

Rodionov

2014

J. Bacteriol.

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bThe DtxR family consists of metal-dependent transcription factors (DtxR-TFs) that regulate the expression of genes involved in metal homeostasis in the cell. The majority of characterized DtxR-TFs belong to Bacteria. In the current work, we applied a comparative genomics approach to predict DNA-binding sites and reconstruct regulons for DtxR-TFs in Archaea. As a result, we inferred 575 candidate binding sites for 139 DtxR-TFs in 77 genomes from 15 taxonomic orders. Novel DNA motifs of archaeal DtxR-TFs that have a common palindromic structure were classified into 10 distinct groups. By combining functional regulon reconstructions with phylogenetic analysis, we selected 28 DtxR-TF clades and assigned them metal specificities and regulator names. The reconstructed FetR (ferrous iron), MntR (manganese), and ZntR (zinc) regulons largely contain known or putative metal uptake transporters from the FeoAB, NRAMP, ZIP, and TroA families. A novel family of putative iron transporters (named Irt), including multiple FetR-regulated paralogs, was identified in iron-oxidizing Archaea from the Sulfolobales order. The reconstructed DtxR-TF regulons were reconciled with available transcriptomics data in Archaeoglobus, Halobacterium, and Thermococcus spp.T ransition metals, including iron, manganese, and zinc, are responsible for a diverse array of biochemical reactions and other biological functions in prokaryotes. The particular properties of ferrous iron (Fe 2ϩ ) and ferric iron (Fe 3ϩ ) ions make them widely used redox-sensing elements in many metalloenzymes, from heme-containing cytochromes to Fe-S proteins. Manganese is used in free radical-detoxifying enzymes, including superoxide dismutase and catalase and some other enzymes. Zinc was found in many proteins, including enzymes of nucleic acid metabolism and ribosomal proteins, where it plays a role in both catalysis and protein structure. Many transition metals are taken up by specific transport systems, including FeoAB family transporters for ferrous iron (1, 2), Fbp-type ATP-binding cassette (ABC) transporters for ferric iron (3), Znu family ABC transporters for zinc (4), and NRAMP family MntR transporters for manganese (5). The precise maintenance of metal ion homeostasis, including metal uptake transporters, is vital for cells that have to balance between supplying enzymes with metal ion cofactors and decreasing the harmful effects of heavy metals (6, 7).The regulation of gene expression by specific binding of transcription factors (TFs) to their DNA sites in response to a cellular signal (e.g., specific metal ions) is a common regulatory mechanism in microorganisms. Iron, manganese, and zinc homeostasis genes in prokaryotes are controlled by TFs from two major families of metalloregulators, Fur and DtxR (8). The ferric uptake regulator Fur and zinc uptake regulator Zur constitute the majority of the Fur family metalloregulators, being widely distributed in diverse lineages of Bacteria but not Archaea, whereas the manganese-and nickel-specific regulators Mur and Nur...

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Comparative Genomics of DtxR Family Regulons for Metal Homeostasis in Archaea

Leyn

Rodionov

2014

J. Bacteriol.

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“…In Corynebacterium spp. and Mycobacterium spp., iron regulation is mediated instead by a functionally similar protein designated DtxR (5,6) or IdeR (7,8), respectively. In the Rhizobiales, iron regulation is mediated in large part by RirA, a member of the Rfr2 family of repressors (9).…”

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The Bacillus subtilis iron-sparing response is mediated by a Fur-regulated small RNA and three small, basic proteins

Gaballa

Antelmann

Aguilar

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

198

240

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Regulation of bacterial iron homeostasis is often controlled by the iron-sensing ferric uptake repressor (Fur). The Bacillus subtilis Fur protein acts as an iron-dependent repressor for siderophore biosynthesis and iron transport proteins. Here, we demonstrate that Fur also coordinates an iron-sparing response that acts to repress the expression of iron-rich proteins when iron is limiting. When Fur is inactive, numerous iron-containing proteins are downregulated, including succinate dehydrogenase, aconitase, cytochromes, and biosynthetic enzymes for heme, cysteine, and branched chain amino acids. As a result, a fur mutant grows slowly in a variety of nutrient conditions. Depending on the growth medium, rapid growth can be restored by mutations in one or more of the molecular effectors of the iron-sparing response. These effectors include the products of three Fur-regulated operons that encode a small RNA (FsrA) and three small, basic proteins (FbpA, FbpB, and FbpC). Extensive complementarity between FsrA and the leader region of the succinate dehydrogenase operon is consistent with an RNA-mediated translational repression mechanism for this target. Thus, iron deprivation in B. subtilis activates pathways to remodel the proteome to preserve iron for the most critical cellular functions.

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“…Moreover, MAB_1080, which was annotated as the porin protein MspD, was also among the genes exhibiting diversity upon chronic infection. Mutations were also identified in ideR , a gene that regulates transcription in response to iron levels [60], as well as in tcrX , which was shown to be up-regulated when M. tuberculosis was grown under iron-limited conditions [29]. Furthermore, Msp porins of rapid growing mycobacteria promote growth in nutrient-limited conditions by enhancing diffusion of small hydrophilic molecules into the cells.…”

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confidence: 99%

Genetic diversification of persistentMycobacterium abscessuswithin Cystic Fibrosis patients

Lewin

Kamal

Semmler

et al. 2021

Preprint

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Mycobacterium (M.) abscessus infections in Cystic Fibrosis (CF) patients cause a deterioration of lung function. Treatment of these multidrug-resistant pathogens is associated with severe side-effects, while frequently unsuccessful. Insight on M. abscessus genomic evolvement during chronic lung infection would be beneficial for improving treatment strategies. A longitudinal study enrolling 42 CF patients was performed at a CF center in Berlin, Germany, to elaborate phylogeny and genomic diversification of in-patient M. abscessus. Eleven of the 42 CF patients were infected with M. abscessus. Global human-transmissible M. abscessus cluster strains were isolated from five of these 11 patients. Phylogenetic analysis of 88 genomes from isolates of the 11 patients excluded occurrence of M. abscessus transmission among members of the study group. Genome sequencing and variant analysis of 30 isolates from 11 serial respiratory samples collected over four years from a chronically infected patient demonstrated accumulation of gene mutations. In total, 53 genes exhibiting non-synonymous variations were identified. Enrichment analysis emphasized genes involved in synthesis of glycopeptidolipids, genes from the embABC (arabinosyltransferase) operon, betA (glucose-methanol-choline oxidoreductase) and choD (cholesterol oxidase). Genetic diversity evolved in a variety of virulence- and resistance-associated genes. The strategy of M. abscessus populations in chronic lung infection is not clonal expansion of dominant variants, but to sustain simultaneously a wide range of genetic variants facilitating adaptation of the population to changing living conditions in the lung. Genomic diversification during chronic infection requires increased attention when new control strategies against M. abscessus infections are explored.

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IdeR in Mycobacteria: From Target Recognition to Physiological Function

Cited by 15 publications

References 59 publications

Comparative Genomics of DtxR Family Regulons for Metal Homeostasis in Archaea

Comparative Genomics of DtxR Family Regulons for Metal Homeostasis in Archaea

The Bacillus subtilis iron-sparing response is mediated by a Fur-regulated small RNA and three small, basic proteins

Genetic diversification of persistentMycobacterium abscessuswithin Cystic Fibrosis patients

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