Abstract:The Haemophilus ducreyi 35000HP genome encodes a homolog of the CpxRA two-component cell envelope stress response system originally characterized in Escherichia coli. CpxR, the cytoplasmic response regulator, was shown previously to be involved in repression of the expression of the lspB-lspA2 operon (M. LabandeiraRey, J. R. Mock, and E. J. Hansen, Infect. Immun. 77:3402-3411, 2009). In the present study, the H. ducreyi CpxR and CpxA proteins were shown to closely resemble those of other well-studied bacterial… Show more
“…Microarray analyses of H. ducreyi and E. coli have shown that Cpx response induction leads to changes in expression of hundreds of genes, including some that are directly regulated by CpxR and many (most) that are not (22,61). Thus, to determine if the above-mentioned genes are bona fide V. cholerae Cpx regulon members and to identify additional candidates that may be regulated indirectly by CpxR, we examined the transcriptional profile of the pandemic strain V. cholerae El Tor C6706 by using a microarray based on the nucleotide sequence of the annotated V. cholerae El Tor strain N16961 (see above).…”
Section: Cholerae Cpxr Regulonmentioning
confidence: 99%
“…For example, in Haemophilus ducreyi, the Cpx response appears not to be as tightly linked to protein misfolding but rather was shown to control the expression of many genes, including several major virulence determinants, predominantly in a negative fashion (22,23). Similarly, for Vibrio cholerae El Tor N16961, recent evidence indicates that the Cpx pathway may be involved in sensing and mediating adaptation to high salinity in addition to responding to misfolded envelope proteins that contain aberrant disulfide bonds (24).…”
The Cpx pathway, a two-component system that employs the sensor histidine kinase CpxA and the response regulator CpxR, regulates crucial envelope stress responses across bacterial species and affects antibiotic resistance. To characterize the CpxR regulon in Vibrio cholerae, the transcriptional profile of the pandemic V. cholerae El Tor C6706 strain was examined upon overexpression of cpxR. Our data show that the Cpx regulon of V. cholerae is enriched in genes encoding membrane-localized and transport proteins, including a large number of genes known or predicted to be iron regulated. Activation of the Cpx pathway further led to the expression of TolC, the major outer membrane pore, and of components of two RND efflux systems in V. cholerae. We show that iron chelation, toxic compounds, or deletion of specific RND efflux components leads to Cpx pathway activation. Furthermore, mutations that eliminate the Cpx response or members of its regulon result in growth phenotypes in the presence of these inducers that, together with Cpx pathway activation, are partially suppressed by iron. Cumulatively, our results suggest that a major function of the Cpx response in V. cholerae is to mediate adaptation to envelope perturbations caused by toxic compounds and the depletion of iron.
Perturbations of the bacterial cell envelope can induce cell envelope stress responses. During this process, signal transduction pathways, such as two-component systems (TCS), are necessary for transducing the information from the cell envelope to the cytoplasm for gene expression regulation (1). TCS are the most prevalent signaling pathways in bacteria, and they are involved in the responses to different inducing cues, mainly related to stress responses and environmental changes (2). The Cpx envelope stress response is an example of a TCS and is composed of the sensor histidine kinase CpxA and the response regulator CpxR (3). This system senses envelope stress and regulates the expression of genes involved in maintaining cell envelope homeostasis to increase bacterial survival under adverse conditions (4).CpxA is an inner membrane (IM) protein that autophosphorylates upon detecting an inducing cue and then becomes a phosphodonor and transfers a phosphoryl group to a conserved aspartate of its response regulator, CpxR (3, 5). CpxR phosphorylation leads to the alteration in transcription of multiple genes by the direct binding of CpxR to DNA (5, 6). In addition, CpxR phosphorylation is modulated indirectly by a periplasmic protein, CpxP, which reduces CpxA activity (6, 7) through a possible direct interaction with the periplasmic sensing domain of CpxA (8-11).The Cpx system in Escherichia coli senses misfolded proteins in the bacterial cell envelope and regulates protein folding and degrading factors, such as DegP, DsbA, and PpiD, involved in the alleviation of the envelope stress (12-15). For example, some of the inducing cues of this pathway are aggregated uropathogenic E. coli P pilus subunits and subunits of the enteropathogenic E. coli bund...
“…Microarray analyses of H. ducreyi and E. coli have shown that Cpx response induction leads to changes in expression of hundreds of genes, including some that are directly regulated by CpxR and many (most) that are not (22,61). Thus, to determine if the above-mentioned genes are bona fide V. cholerae Cpx regulon members and to identify additional candidates that may be regulated indirectly by CpxR, we examined the transcriptional profile of the pandemic strain V. cholerae El Tor C6706 by using a microarray based on the nucleotide sequence of the annotated V. cholerae El Tor strain N16961 (see above).…”
Section: Cholerae Cpxr Regulonmentioning
confidence: 99%
“…For example, in Haemophilus ducreyi, the Cpx response appears not to be as tightly linked to protein misfolding but rather was shown to control the expression of many genes, including several major virulence determinants, predominantly in a negative fashion (22,23). Similarly, for Vibrio cholerae El Tor N16961, recent evidence indicates that the Cpx pathway may be involved in sensing and mediating adaptation to high salinity in addition to responding to misfolded envelope proteins that contain aberrant disulfide bonds (24).…”
The Cpx pathway, a two-component system that employs the sensor histidine kinase CpxA and the response regulator CpxR, regulates crucial envelope stress responses across bacterial species and affects antibiotic resistance. To characterize the CpxR regulon in Vibrio cholerae, the transcriptional profile of the pandemic V. cholerae El Tor C6706 strain was examined upon overexpression of cpxR. Our data show that the Cpx regulon of V. cholerae is enriched in genes encoding membrane-localized and transport proteins, including a large number of genes known or predicted to be iron regulated. Activation of the Cpx pathway further led to the expression of TolC, the major outer membrane pore, and of components of two RND efflux systems in V. cholerae. We show that iron chelation, toxic compounds, or deletion of specific RND efflux components leads to Cpx pathway activation. Furthermore, mutations that eliminate the Cpx response or members of its regulon result in growth phenotypes in the presence of these inducers that, together with Cpx pathway activation, are partially suppressed by iron. Cumulatively, our results suggest that a major function of the Cpx response in V. cholerae is to mediate adaptation to envelope perturbations caused by toxic compounds and the depletion of iron.
Perturbations of the bacterial cell envelope can induce cell envelope stress responses. During this process, signal transduction pathways, such as two-component systems (TCS), are necessary for transducing the information from the cell envelope to the cytoplasm for gene expression regulation (1). TCS are the most prevalent signaling pathways in bacteria, and they are involved in the responses to different inducing cues, mainly related to stress responses and environmental changes (2). The Cpx envelope stress response is an example of a TCS and is composed of the sensor histidine kinase CpxA and the response regulator CpxR (3). This system senses envelope stress and regulates the expression of genes involved in maintaining cell envelope homeostasis to increase bacterial survival under adverse conditions (4).CpxA is an inner membrane (IM) protein that autophosphorylates upon detecting an inducing cue and then becomes a phosphodonor and transfers a phosphoryl group to a conserved aspartate of its response regulator, CpxR (3, 5). CpxR phosphorylation leads to the alteration in transcription of multiple genes by the direct binding of CpxR to DNA (5, 6). In addition, CpxR phosphorylation is modulated indirectly by a periplasmic protein, CpxP, which reduces CpxA activity (6, 7) through a possible direct interaction with the periplasmic sensing domain of CpxA (8-11).The Cpx system in Escherichia coli senses misfolded proteins in the bacterial cell envelope and regulates protein folding and degrading factors, such as DegP, DsbA, and PpiD, involved in the alleviation of the envelope stress (12-15). For example, some of the inducing cues of this pathway are aggregated uropathogenic E. coli P pilus subunits and subunits of the enteropathogenic E. coli bund...
“…Self-autoagglutination is an indirect indicator of bacterial colonization and virulence in vivo [22,43]. Here, we observed that the autoagglutination ability of the ΔlsgB mutant was significantly decreased, and we also demonstrated a significant attenuation of in vivo pathogenicity, as well as reduced colonization and survival of the ΔlsgB mutant, compared to the wild-type and complementation strains.…”
Section: Discussionmentioning
confidence: 59%
“…Bacterial autoagglutination is a potential virulence-associated indicator in some Gram-negative bacteria [22]; therefore, we next considered whether lsgB gene deletion affects bacterial virulence. In the autoagglutination test, the upper suspension of the static ΔlsgB culture rapidly decreased with time (Figure 4(a)) and most bacteria had precipitated to the bottom of the culture after incubation for 6 h (Figure 4(b)), indicating significantly attenuated autoagglutination of the ΔlsgB mutant compared with the wild-type and C- lsgB strains.10.1080/21505594.2018.1502606-F0004Figure 4. H. parasuis lsgB deletion attenuates bacterial autoagglutination and pathogenicity, and colonization and survival in vivo .…”
Section: Resultsmentioning
confidence: 99%
“…The autoagglutination ability of H. parasuis wild-type, ΔlsgB mutant and C- lsgB strains was evaluated as previously described with slight modifications [22]. Briefly, overnight cultures of each strain were inoculated into 5mL of TSB/V/S medium and cultured at 37°C for 10 h. Bacterial cells were collected and diluted in fresh medium to OD 600 0.7, and the mixture was subsequently statically incubated at 25°C.…”
Bacterial lipooligosaccharide (LOS) is an important virulence-associated factor, and its sialylation largely confers its ability to mediate cell adhesion, invasion, inflammation, and immune evasion. Here, we investigated the function of the Haemophilus parasuis α-2,3-sialyltransferase gene, lsgB, which determines the terminal sialylation of LOS, by generating a lsgB deletion mutant as well as a complementation strain. Our data indicate a direct effect of lsgB on LOS sialylation and reveal important roles of lsgB in promoting the pathogenicity of H. parasuis, including adhesion to and invasion of porcine cells in vitro, bacterial load and survival in vivo, as well as a contribution to serum resistance. These observations highlight the function of lsgB in mediating LOS sialylation and more importantly its role in H. parasuis infection. These findings provide a more profound understanding of the pathogenic mechanism of this disease-causing bacterium.
The Cpx envelope stress response (ESR) has been linked to proteins that are integrated into and secreted across the inner membrane for several decades. Initial studies of the cpx locus linked it to alterations in the protein content of both the inner and outer membrane, together with changes in proton motive driven transport and conjugation. Since the mid 1990s, the predominant view of the Cpx envelope stress response has been that it serves to detect and respond to secreted, misfolded proteins in the periplasm. Recent studies in Escherichia coli and other Gram negative organisms highlight a role for the Cpx ESR in specifically responding to perturbations that occur at the inner membrane (IM). It is clear that Cpx adaptation involves a broad suite of changes that encompass many functions in addition to protein folding. Interestingly, recent studies have refocused attention on Cpx-regulated phenotypes that were initially published over 30years ago, including antibiotic resistance and transport across the IM. In this review I will focus on the insights and models that have arisen from recent studies and that may help explain some of the originally published Cpx phenotypes. Although the molecular nature of the inducing signal for the Cpx ESR remains enigmatic, recently solved structures of signaling proteins are yielding testable models concerning the molecular mechanisms behind signaling. The identification of connections between the Cpx ESR and other stress responses in the cell reveals a complex web of interactions that involves Cpx-regulated expression of other regulators as well as small proteins and sRNAs. This article is part of a Special Issue entitled: Protein trafficking and secretion in bacteria. Guest Editors: Anastassios Economou and Ross Dalbey.
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