Fur functions as an activator and as a repressor of putative virulence genes in <i>Neisseria meningitidis</i>

Delany, Isabel; Rappuoli, Rino; Scarlato, Vincenzo

doi:10.1111/j.1365-2958.2004.04030.x

Cited by 170 publications

(166 citation statements)

References 44 publications

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“…The involvement of Fur in nitrogen metabolism has been reported in other bacteria. The Fur protein in Neisseria meningitidis activates the pan1 and norB genes, which encode nitrite and NO reductases, respectively (Delany et al, 2004), and the E. coli fur mutant exhibits a severe growth delay under aerobic conditions in the presence of nitrosylated glutathione or acidified nitrite (Mukhopadhyay et al, 2004). In contrast, we showed in this study that the fur mutation in strain ATCC 17616 causes hypersensitivity to nitrite under microaerobic conditions and also acidified nitrite (an NO producer) under aerobic conditions.…”

Section: Discussioncontrasting

confidence: 44%

Pleiotropic roles of iron-responsive transcriptional regulator Fur in Burkholderia multivorans

et al. 2008

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The fur (ferric uptake regulator) gene of Burkholderia multivorans ATCC 17616 was identified by transposon mutagenesis analysis. The fur deletion mutant of strain ATCC 17616 (i) constitutively produced siderophores, (ii) was more sensitive to reactive oxygen species (ROS) than the wild-type strain, (iii) showed lower superoxide dismutase and catalase activities than the wild-type strain, (iv) was unable to grow on M9 minimal agar plates containing several substrates that can be used as sole carbon sources by the wild-type strain, and (v) was hypersensitive to nitrite and nitric oxide under microaerobic and aerobic conditions, respectively. These results clearly indicate that the Fur protein in strain ATCC 17616 plays pleiotropic roles in iron homeostasis, removal and/or resistance to ROS and nitrosative stress, and energy metabolism. Furthermore, employment of an in vivo Fur titration assay system led to the isolation from the ATCC 17616 genome of 13 Fur-binding DNA regions, and a subsequent electrophoretic mobility-shift assay confirmed the direct binding of Fur protein to all of these DNA regions. Transcriptional analysis of the genes located just downstream of the Fur-binding sites demonstrated that Fur acts as a repressor for these genes. Nine of the 13 regions were presumed to be involved in the acquisition and utilization of iron.

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Section: Discussioncontrasting

confidence: 44%

Pleiotropic roles of iron-responsive transcriptional regulator Fur in Burkholderia multivorans

et al. 2008

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“…There have been several reports that norB is activated by Fur aerobically (Sebastian et al, 2002;Grifantini et al, 2003Grifantini et al, , 2004; however, most of the data that support a role for Fur in activation of norB are based on demonstrating that Fur can bind to the site. In an in vitro transcription assay, Delany et al (2004) provide evidence that Fur may directly activate the meningococcal norB promoter, although our in vivo translational fusion analysis of the gonococcal norB upstream region shows no direct Fur activation (Fig. 1).…”

Section: Discussionmentioning

confidence: 99%

“…Elimination of the Fur binding site in RUG7512 suggested that Fur had no role in the regulation of norB, despite several reports to the contrary in N. gonorrhoeae (Sebastian et al, 2002) and N. meningitidis (Grifantini et al, 2003(Grifantini et al, , 2004Delany et al, 2004). We therefore investigated the expression of norB : : lacZ fusions in a Dfur mutant (Fig.…”

Section: Indirect Regulation Of Norb By Furmentioning

confidence: 99%

cis- and trans-acting elements involved in regulation of norB (norZ), the gene encoding nitric oxide reductase in Neisseria gonorrhoeae

et al. 2008

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The ability of Neisseria gonorrhoeae to reduce nitric oxide (NO) may have important immunomodulatory effects on the host during infection. Therefore, a comprehensive understanding of the regulatory mechanism of the nitric oxide reductase gene (norB) needs to be elucidated. To accomplish this, we analysed the functional regions of the norB upstream region. The promoter contains an extended "10 motif (TGNTACAAT) that is required for high-level expression. Deletion and substitution analysis of the norB upstream region revealed that no sequence upstream of the "10 motif is involved in norB regulation under anaerobic conditions or in the presence of NO. However, replacement of a 29 bp inverted repeat sequence immediately downstream of the extended "10 motif gave high levels of aerobic expression of a norB : : lacZ fusion. Insertional inactivation of gonococcal nsrR, predicted to bind to this inverted repeat sequence, resulted in the loss of norB repression and eliminated NO induction capacity. Single-copy complementation of nsrR in trans restored regulation of both norB transcription and NorB activity by NO. In Escherichia coli, expression of a gonococcal nsrR gene repressed gonococcal norB; induction of norB occurred in the presence of exogenously added NO. NsrR also regulates aniA and dnrN, as well as its own expression. We also determined that Fur regulates norB by a novel indirect activation method, by preventing the binding of a gonococcal ArsR homologue, a second repressor whose putative binding site overlaps the Fur binding site.

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“…IHF is a histone-like protein involved in the condensation of the bacterial chromosomal DNA that has been shown to act as a transcriptional regulator (14,15). Fur has been shown to mediate transcriptional regulation of numerous bacterial virulence factors in response to iron (16)(17)(18).…”

Section: Resultsmentioning

confidence: 99%

“…The histone-like protein IHF was shown to be involved in the regulation of the expression of the type IV pilus that is necessary for the establishment of the colonization of the mucosal surfaces by the meningococcus (18,19). Although it was shown in Escherichia coli that Fur and the regulatory factors H-NS and IHF cooperate to regulate the expression of the gene encoding the iron superoxide dismutase (20), in N. meningitidis the nadA gene is the first indication of a gene that is apparently regulated by both IHF and Fur.…”

Section: Discussionmentioning

confidence: 99%

Microsatellite instability regulates transcription factor binding and gene expression

Martín

Makepeace

Hill

et al. 2005

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

168

125

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Microsatellites are tandemly repeated simple sequence DNA motifs widely prevalent in eukaryotic and prokaryotic genomes. In pathogenic bacteria, instability of these hypermutable loci through slipped-strand mispairing mediates the high-frequency reversible switching of phenotype expression, i.e., phase variation. Phasevariable expression of NadA, an outer membrane protein and adhesin of the pathogen Neisseria meningitidis, is mediated by changes in the number of TAAA repeats located upstream of the core promoter of nadA. Here we report that loss or gain of TAAA repeats affects the binding of the transcriptional regulatory protein IHF to the nadA promoter. Thus, phase-variable transcription of nadA potentially incorporates interplay between stochastic (mutational) and prescriptive (classical) mechanisms of gene regulation.phase variation N eisseria meningitidis is a Gram-negative encapsulated bacterium predominantly found in the human nasopharynx, where it can be a constituent of the normal microbial f lora. However, some strains are invasive and penetrate first the blood and then the meninges to cause septicemia and meningitis. N. meningitidis has evolved several environmentally induced regulatory systems to control the expression of the virulence factors that are differentially expressed during the establishment of the infection (1-3). Phase variation, which results in high-frequency switching of phenotype expression, relies on environment-independent stochastic changes occurring within repeated simple sequence DNA motifs located in coding or promoter regions of numerous genes potentially involved in pathogenicity (4). Addition or subtraction of repeated units creates frameshifts and premature stop codons (5) or alters the strength of the promoter (6 -8).The nadA gene, which encodes an outer membrane protein and adhesin (9), was recently shown to be present in 50% of the disease-associated N. meningitidis strains and in 100% of the strains belonging to hypervirulent lineages ET-5, ET-37, and cluster A4, but in only 16% of the strains isolated from healthy people (10). NadA is currently under investigation as a vaccine candidate (11). The phase-variable expression of the nadA gene was recently shown to be regulated at the transcriptional level through a variation of the number of reiterated TAAA motifs present in the repeat tract located upstream of the core promoter of the gene (12).Here we investigate the mechanism of phase variation of NadA, and in particular, the role of the TAAA microsatellite in transcriptional regulation. We show that both the TAAA repeat tract and the sequence located upstream of the microsatellite are involved in varying transcriptional activity and that the nadA promoter region also possesses multiple integration host factor (IHF)-and ferric uptake regulatory protein (Fur)-binding sites. Further, changes in the number of TAAA repeats, a requisite for phase variation, alter the binding of IHF to the nadA promoter. Thus transcription of nadA involves an interplay between mutation (slippa...

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Fur functions as an activator and as a repressor of putative virulence genes in Neisseria meningitidis

Cited by 170 publications

References 44 publications

Pleiotropic roles of iron-responsive transcriptional regulator Fur in Burkholderia multivorans

Pleiotropic roles of iron-responsive transcriptional regulator Fur in Burkholderia multivorans

cis- and trans-acting elements involved in regulation of norB (norZ), the gene encoding nitric oxide reductase in Neisseria gonorrhoeae

Microsatellite instability regulates transcription factor binding and gene expression

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