The Nitric Oxide (NO)-Sensing Repressor NsrR of
            <i>Neisseria meningitidis</i>
            Has a Compact Regulon of Genes Involved in NO Synthesis and Detoxification

Heurlier, Karin; Thomson, Melanie J.; Aziz, Naveed; Moir, James

doi:10.1128/jb.01869-07

Cited by 58 publications

(59 citation statements)

References 43 publications

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“…NO has a half life of a few seconds, so the study of its effects on P. gingivalis required the use of a NO donor (12) to maintain exposure of the bacterial cells to the compound. Among many methods (30,31,43,44,48,56), DEA NONOate had been successfully used in studies involving bacteria (42) and had a short enough half life to avoid unnecessary prolonged bacterial exposure to NO and allow us to determine easily the dose needed to replicate NO levels found in the periodontal pocket (47). Our studies revealed that, to mimic the average NO physiological range of periodontal pockets, the ideal DEA NONOate dose in hypoxic BHI was 10 l of 36 mM, or 0.36 mol.…”

Section: Resultsmentioning

confidence: 98%

Nitric Oxide Stress Resistance in Porphyromonas gingivalis Is Mediated by a Putative Hydroxylamine Reductase

et al. 2012

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bPorphyromonas gingivalis, the causative agent of adult periodontitis, must maintain nitric oxide (NO) homeostasis and surmount nitric oxide stress from host immune responses or other oral bacteria to survive in the periodontal pocket. To determine the involvement of a putative hydroxylamine reductase (PG0893) and a putative nitrite reductase-related protein (PG2213) in P. gingivalis W83 NO stress resistance, genes encoding those proteins were inactivated by allelic exchange mutagenesis. The isogenic mutants P. gingivalis FLL455 (PG0893::ermF) and FLL456 (PG2213::ermF) were black pigmented and showed growth rates and gingipain and hemolytic activities similar to those of the wild-type strain. P. gingivalis FLL455 was more sensitive to NO than the wild type. Complementation of P. gingivalis FLL455 with the wild-type gene restored the level of NO sensitivity to a level similar to that of the parent strain. P. gingivalis FLL455 and FLL456 showed sensitivity to oxidative stress similar to that of the wild-type strain. DNA microarray analysis showed that PG0893 and PG2213 were upregulated 1.4-and 2-fold, respectively, in cells exposed to NO. In addition, 178 genes were upregulated and 201 genes downregulated more than 2-fold. The majority of these modulated genes were hypothetical or of unknown function. PG1181, predicted to encode a transcriptional regulator, was upregulated 76-fold. Transcriptome in silico analysis of the microarray data showed major metabolomic variations in key pathways. Collectively, these findings indicate that PG0893 and several other genes may play an important role in P. gingivalis NO stress resistance. Porphyromonas gingivalis is a Gram-negative anaerobic bacterium that is a primary etiologic agent of periodontal disease. This infection-induced disease is characterized by inflammation, which can result in host-mediated destruction of tooth-supporting tissues and structures (18). Nitric oxide (NO) is a key component of the host immune response. Oral neutrophils can constitutively secrete low concentrations of NO via the involvement of multiple NO synthases. However, with activation, these neutrophils have increased secretion of NO with antimicrobial effects. As in other host-pathogen interactions (22), P. gingivalis has been shown to trigger the production of NO in immune and nonimmune host cells by activating the expression of inducible nitric oxide synthases (9, 54) and can survive in NO concentrations ranging from 4.9 M to 19.2 M (47). Elevated NO concentrations are reported to cause vasodilatation and a decrease in platelet aggregation, which may contribute to gingival bleeding (18), and to have cytotoxic effects on surrounding host tissue that can lead to alveolar bone loss (7). NO is present in the saliva and gingival fluid of periodontitis patients (7,18,57). Further, saliva NO concentrations have been shown to increase with the severity of periodontitis (47).P. gingivalis, as an asaccharolytic microorganism, metabolizes nitrogenous compounds as a source of energy and generates a micr...

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Section: Resultsmentioning

confidence: 98%

Nitric Oxide Stress Resistance in Porphyromonas gingivalis Is Mediated by a Putative Hydroxylamine Reductase

et al. 2012

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“…Transcriptome analyses in diverse bacteria have indicated that the regulon of NsrR is relatively small (less than 10 genes) in the case of Neisseria meningitidis (27) and Moraxella catarrhalis (61), moderate (20 genes downregulated by NsrR) in E. coli (18), and large in Streptomyces (over 300 predicted target genes [60]). Previous studies have presented evidence that NsrR transcriptional regulation is modulated at the posttranslational level, namely, by modification of Fe-S clusters in NsrR by NO (29,31).…”

Section: Discussionmentioning

confidence: 99%

Global Transcriptional Control by NsrR in Bacillus subtilis

et al. 2012

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The NO-sensitive NsrR repressor of Bacillus subtilis, which carries a [4Fe-4S] cluster, controls transcription of nasD and hmp (class I regulation) under anaerobic conditions. Here, we describe another class of NsrR regulation (class II regulation) that controls a more diverse collection of genes. Base substitution analysis showed that [4Fe-4S]-NsrR recognizes a partial dyad symmetry within the class I cis-acting sites, whereas NO-insensitive interaction of NsrR with an A؉T-rich class II regulatory site showed relaxed sequence specificity. Genome-wide transcriptome studies identified genes that are under the control of the class II NsrR regulation. The class II NsrR regulon includes genes controlled by both AbrB and Rok repressors, which also recognize A؉T-rich sequences, and by the Fur repressor. Transcription of class II genes was elevated in an nsrR mutant during anaerobic fermentative growth with pyruvate. Although NsrR binding to the class II regulatory sites was NO insensitive in vitro, transcription of class II genes was moderately induced by NO, which involved reversal of NsrR-dependent repression, suggesting that class II repression is also NO sensitive. In all NsrR-repressed genes tested, the loss of NsrR repressor activity was not sufficient to induce transcription as induction required the ResD response regulator. The ResD-ResE signal transduction system is essential for activation of genes involved in aerobic and anaerobic respiration. This study indicated coordinated regulation between ResD and NsrR and uncovered a new role of ResD and NsrR in transcriptional regulation during anaerobiosis of B. subtilis. N itric oxide (NO) has been shown to function as a signal molecule in bacterial physiology, but it can be toxic at high concentrations (17). Therefore, bacteria have developed elaborate regulatory mechanisms to sense and detoxify NO. The NsrR transcriptional control plays a role in the NO stress response as a repressor in 24,29,49,61) and Gram-positive (38, 59) bacteria. Flavohemoglobin Hmp is often specified by a gene controlled by NsrR among diverse bacteria (50). Hmp is required for Salmonella virulence in mice (6) and for its survival in a macrophage cell line (24). Hmp detoxifies NO by converting it to nitrate under aerobic conditions (21, 26). Other genes controlled by NsrR include those involved in NO metabolism and detoxification (summarized in reference 60), as predicted in a comparative genomics study (50). Furthermore, recent studies showed that NsrR controls NO-induced expression of NO-resistant alternative oxidase (Aox) in Vibrio fischeri, thus supporting bacterial growth during NO stress (14).NsrR is an [Fe-S] cluster-bearing protein, and binding of NsrR to its target genes is relieved in the presence of NO, leading to an upregulation (reviewed in reference 60). The mechanism by which NsrR controls transcription of genes in response to NO has been investigated in vitro. NsrR from Neisseria gonorrhoeae (29) and Streptomyces coelicolor (59) was shown to contain a [2Fe-2S] cluster when ...

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“…In the context of the current work, the regulator of interest is NsrR, a transcriptional repressor from the Rrf2 family, which probably contains an iron-sulfur cluster and is sensitive to sources of NO. NsrR has been shown to act as an NO-sensitive regulator of gene expression in several organisms (1,2,5,14,17,19,28,31,33), and targets for NsrR regulation have been predicted (34). In E. coli, NsrR regulates expression of the NO-detoxifying flavohemoglobin, along with several other genes and operons, some of which are of unknown or poorly understood function (5,13,24,40).…”

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confidence: 99%

Escherichia coli NsrR Regulates a Pathway for the Oxidation of 3-Nitrotyramine to 4-Hydroxy-3-Nitrophenylacetate

Rankin

Bodenmiller²,

Partridge

et al. 2008

J Bacteriol

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Chromatin immunoprecipitation and microarray (ChIP-chip) analysis showed that the nitric oxide (NO)-sensitive repressor NsrR from Escherichia coli binds in vivo to the promoters of the tynA and feaB genes. These genes encode the first two enzymes of a pathway that is required for the catabolism of phenylethylamine (PEA) and its hydroxylated derivatives tyramine and dopamine. Deletion of nsrR caused small increases in the activities of the tynA and feaB promoters in cultures grown on PEA. Overexpression of nsrR severely retarded growth on PEA and caused a marked repression of the tynA and feaB promoters. Both the growth defect and the promoter repression were reversed in the presence of a source of NO. These results are consistent with NsrR mediating repression of the tynA and feaB genes by binding (in an NO-sensitive fashion) to the sites identified by ChIP-chip. E. coli was shown to use 3-nitrotyramine as a nitrogen source for growth, conditions which partially induce the tynA and feaB promoters. Mutation of tynA (but not feaB) prevented growth on 3-nitrotyramine. Growth yields, mutant phenotypes, and analyses of culture supernatants suggested that 3-nitrotyramine is oxidized to 4-hydroxy-3-nitrophenylacetate, with growth occurring at the expense of the amino group of 3-nitrotyramine. Accordingly, enzyme assays showed that 3-nitrotyramine and its oxidation product (4-hydroxy-3-nitrophenylacetaldehyde) could be oxidized by the enzymes encoded by tynA and feaB, respectively. The results suggest that an additional physiological role of the PEA catabolic pathway is to metabolize nitroaromatic compounds that may accumulate in cells exposed to NO.

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The Nitric Oxide (NO)-Sensing Repressor NsrR of Neisseria meningitidis Has a Compact Regulon of Genes Involved in NO Synthesis and Detoxification

Cited by 58 publications

References 43 publications

Nitric Oxide Stress Resistance in Porphyromonas gingivalis Is Mediated by a Putative Hydroxylamine Reductase

Nitric Oxide Stress Resistance in Porphyromonas gingivalis Is Mediated by a Putative Hydroxylamine Reductase

Global Transcriptional Control by NsrR in Bacillus subtilis

Escherichia coli NsrR Regulates a Pathway for the Oxidation of 3-Nitrotyramine to 4-Hydroxy-3-Nitrophenylacetate

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