Deciphering Fur transcriptional regulatory network highlights its complex role beyond iron metabolism in Escherichia coli

Seo, Sang Woo; Kim, Donghyuk; Latif, Haythem; O’Brien, Edward J.; Szubin, Richard; Palsson, Bernhard Ø.

doi:10.1038/ncomms5910

Cited by 269 publications

(352 citation statements)

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“…An interesting finding of our work was the altered expression levels of several genes that belong to the Fur regulon (42)(43)(44). The CHP-mediated upregulation of Furrepressed genes and downregulation of Fur-activated genes suggest that CHP may affect the Fur protein.…”

Section: Discussionmentioning

confidence: 76%

“…CHPupregulated iron acquisition systems included outer membrane TonB-dependent receptors (CV_0077, CV_1491, CV_1982, CV_3896, fepA, and fhuA), energy-transducing TonB-ExbB-ExbD protein complexes (CV_0400-CV_0399-CV_0398, CV_1971-CV_1972- CV_1973-CV_1974, CV_1983, CV_1986, and CV_4254), ABC transporters (CV_3895-CV_3896-CV_3897-CV_3898-CV_3899, CV_1491-CV_1490-CV_1489-CV_1488-CV_1487, and CV_2236-CV_2235-CV_2234), and enzymes for the synthesis of iron-chelating molecules such as riboflavin (CV_2387-CV_2388-CV_2389) and the siderophore enterobactin (entFCEBA and CV_2231-CV_2232-CV_2233). As the above-mentioned genes are members of the Fur regulon in many bacteria (42)(43)(44) and the C. violaceum genome encodes the Fur protein (21), we hypothesize that CHP is derepressing the Fur regulon. CHP could be causing either direct iron starvation due to a reaction with Fe(II) (45) or the oxidation of the holo-Fur protein, disrupting its DNA binding activity (46).…”

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confidence: 99%

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Global Transcriptional Response to Organic Hydroperoxide and the Role of OhrR in the Control of Virulence Traits in Chromobacterium violaceum

et al. 2017

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A major pathway for the detoxification of organic hydroperoxides, such as cumene hydroperoxide (CHP), involves the MarR family transcriptional regulator OhrR and the peroxidase OhrA. However, the effect of these peroxides on the global transcriptome and the contribution of the OhrA/OhrR system to bacterial virulence remain poorly explored. Here, we analyzed the transcriptome profiles of Chromobacterium violaceum exposed to CHP and after the deletion of ohrR, and we show that OhrR controls the virulence of this human opportunistic pathogen. DNA microarray and Northern blot analyses of CHP-treated cells revealed the upregulation of genes related to the detoxification of peroxides (antioxidant enzymes and thiol-reducing systems), the degradation of the aromatic moiety of CHP (oxygenases), and protection against other secondary stresses (DNA repair, heat shock, iron limitation, and nitrogen starvation responses). Furthermore, we identified two upregulated genes (ohrA and a putative diguanylate cyclase with a GGDEF domain for cyclic di-GMP [c-di-GMP] synthesis) and three downregulated genes (hemolysin, chitinase, and collagenase) in the ohrR mutant by transcriptome analysis. Importantly, we show that OhrR directly repressed the expression of the putative diguanylate cyclase. Using a mouse infection model, we demonstrate that the ohrR mutant was attenuated for virulence and showed a decreased bacterial burden in the liver. Moreover, an ohrRdiguanylate cyclase double mutant displayed the same virulence as the wild-type strain. In conclusion, we have defined the transcriptional response to CHP, identified potential virulence factors such as diguanylate cyclase as members of the OhrR regulon, and shown that C. violaceum uses the transcriptional regulator OhrR to modulate its virulence.KEYWORDS oxidative stress, organic hydroperoxides, CHP stimulon, OhrA/OhrR system, MarR family, bacterial virulence, cumene hydroperoxide, diguanylate cyclase, transcription factors B acteria are exposed to reactive oxygen species (ROS) generated endogenously or produced by phagocytic cells from the mammalian immune system (1-3). Other harmful oxidants are organic hydroperoxides (OHPs) produced either enzymatically during eicosanoid metabolism (4) or by the free radical-catalyzed oxidation of polyunsaturated fatty acids (PUFAs) during lipid peroxidation (5). In the lipid peroxidation process, multiple toxic breakdown molecules are generated, including lipid hydroperoxides (LHPs) and short-chain aldehydes such as malondialdehyde (MDA) (5, 6). Because bacterial membranes are usually devoid of PUFAs and contain mainly saturated fatty acids and monounsaturated fatty acids (UFAs) (7), lipid peroxidation in bacteria is

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Section: Discussionmentioning

confidence: 76%

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confidence: 99%

Global Transcriptional Response to Organic Hydroperoxide and the Role of OhrR in the Control of Virulence Traits in Chromobacterium violaceum

et al. 2017

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“…Many Fur homologues have been shown to be global regulators that affect metabolism, motility, stress responses, biofilm formation, and pathogenicity (19)(20)(21)(22)(23)(24). While most Fur family members recognize palindromic DNA sequences that follow the 7-1-7 rule (i.e., a 1-bp spacer separating a pair of 7-bp palindromic sequences) (11,23), variations to this rule have been reported (6,25).…”

mentioning

confidence: 99%

“…While most Fur family members recognize palindromic DNA sequences that follow the 7-1-7 rule (i.e., a 1-bp spacer separating a pair of 7-bp palindromic sequences) (11,23), variations to this rule have been reported (6,25). Two recent genome-wide studies of Campylobacter jejuni and E. coli Fur regulons suggest that the consensus sequences targeted for activation could differ significantly from those targeted for repression and may not even be palindromic (22,24).…”

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confidence: 99%

BosR Is A Novel Fur Family Member Responsive to Copper and Regulating Copper Homeostasis in Borrelia burgdorferi

Wang

Santangelo

et al. 2017

J Bacteriol

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The ferric uptake regulator (Fur) family of DNA-binding proteins represses and/or activates gene transcription via divalent metal ion-dependent signal sensing. The Borrelia burgdorferi Fur homologue, also known as Borrelia oxidative stress regulator (BosR), promotes spirochetal adaptation to the mammalian host by directly repressing the lipoproteins required for tick colonization and indirectly activating those required for establishing infection in the mammal. Here, we examined whether the DNA-binding activity of BosR was regulated by any of the four most prevalent transition metal ions in B. burgdorferi, Mn, Fe, Cu, and Zn. Our data indicated that in addition to a structural site occupied by Zn(II), BosR had two regulatory sites that could be occupied by Zn(II), Fe(II), or Cu(II) but not by Mn(II). While Fe(II) had no effect, Cu(II) and Zn(II) had a dose-dependent inhibitory effect on the BosR DNA-binding activity. Competition experiments indicated that Cu(II) had a higher affinity for BosR than Zn(II) or Fe(II). A BosR deficiency in B. burgdorferi resulted in a significant increase in the Cu level but no significant change in the levels of Mn, Fe, or Zn. These data suggest that Cu regulates BosR activity, and BosR in turn regulates Cu homeostasis in B. burgdorferi. While this regulatory paradigm is characteristic of the Fur family, BosR is the first one shown to be responsive to Cu(II), which may be an adaptation to the potentially high level of Cu present in the Lyme disease spirochete. IMPORTANCE Transition metal ions serve an essential role in the metabolism of all living organisms. Members of the ferric uptake regulator (Fur) family play critical roles in regulating the cellular homeostasis of transition metals in diverse bacteria, and their DNA-binding activity is often regulated by coordination of the cognate divalent metal ions. To date, regulators with metal ion specificity to Fe(II), Mn(II), Zn(II), and Ni(II) have all been described. In this study, we demonstrate that BosR, the sole Fur homologue in Borrelia burgdorferi, is responsive to Cu(II) and regulates Cu homeostasis in this bacterium, which may be an adaption to potentially Cu-rich milieu in the Lyme disease spirochete. This study has expanded the repertoire of the Fur family's metal ion specificity.

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“…In E. coli, changes in cytosolic iron concentrations are directly sensed by Fur (36). When bound to Fe 2ϩ , Fur acts as a transcription factor, regulating genes involved in diverse cellular processes, such as metabolism, metal acquisition, stress responses, motility, and biofilm formation (37,38). Changes in extracellular iron concentrations are also sensed by the membrane-associated kinase BasS, a member of the BasRS two-component system (39).…”

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confidence: 99%

Adherent-Invasive Escherichia coli Production of Cellulose Influences Iron-Induced Bacterial Aggregation, Phagocytosis, and Induction of Colitis

et al. 2015

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Adherent-invasive Escherichia coli (AIEC), a functionally distinct subset of resident intestinal E. coli associated with Crohn's disease, is characterized by enhanced epithelial adhesion and invasion, survival within macrophages, and biofilm formation. Environmental factors, such as iron, modulate E. coli production of extracellular structures, which in turn influence the formation of multicellular communities, such as biofilms, and bacterial interactions with host cells. However, the physiological and functional responses of AIEC to variable iron availability have not been thoroughly investigated. We therefore characterized the impact of iron on the physiology of AIEC strain NC101 and subsequent interactions with macrophages. Iron promoted the cellulose-dependent aggregation of NC101. Bacterial cells recovered from the aggregates were more susceptible to phagocytosis than planktonic cells, which corresponded with the decreased macrophage production of the proinflammatory cytokine interleukin-12 (IL-12) p40. Prevention of aggregate formation through the disruption of cellulose production reduced the phagocytosis of iron-exposed NC101. In contrast, under iron-limiting conditions, where NC101 aggregation is not induced, the disruption of cellulose production enhanced NC101 phagocytosis and decreased macrophage secretion of IL-12 p40. Finally, abrogation of cellulose production reduced NC101 induction of colitis when NC101 was monoassociated in inflammation-prone Il10 ؊/؊ mice. Taken together, our results introduce cellulose as a novel physiological factor that impacts host-microbe-environment interactions and alters the proinflammatory potential of AIEC.

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Deciphering Fur transcriptional regulatory network highlights its complex role beyond iron metabolism in Escherichia coli

Cited by 269 publications

References 50 publications

Global Transcriptional Response to Organic Hydroperoxide and the Role of OhrR in the Control of Virulence Traits in Chromobacterium violaceum

Global Transcriptional Response to Organic Hydroperoxide and the Role of OhrR in the Control of Virulence Traits in Chromobacterium violaceum

BosR Is A Novel Fur Family Member Responsive to Copper and Regulating Copper Homeostasis in Borrelia burgdorferi

Adherent-Invasive Escherichia coli Production of Cellulose Influences Iron-Induced Bacterial Aggregation, Phagocytosis, and Induction of Colitis

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