The Response Regulator CpxR Directly Regulates Expression of Several<i>Legionella pneumophila icm/dot</i>Components as Well as New Translocated Substrates

Altman, Efrat; Segal, G. M.

doi:10.1128/jb.01493-07

Cited by 101 publications

(144 citation statements)

References 64 publications

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“…Formation of the Legionella-containing vacuole (LCV) requires a functional type IV secretion system (T4SS) known as the Icm/Dot complex (8,9), which transports a massive collection of effectors into the host cytosol. To date, over 275 of these protein substrates have been identified (10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Shortly after internalization of the bacteria into either macrophages or amoebae, mitochondria and markers of the endoplasmic reticulum are recruited to the LCV to establish a vacuole that allows replication before the cell lyses, releasing bacteria into the extracellular milieu for a second round of infection (20)(21)(22).…”

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confidence: 99%

Poison Domains Block Transit of Translocated Substrates via the Legionella pneumophila Icm/Dot System

2013

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Legionella pneumophila uses the Icm/Dot type 4B secretion system (T4BSS) to deliver translocated protein substrates to the host cell, promoting replication vacuole formation. The conformational state of the translocated substrates within the bacterial cell is unknown, so we sought to determine if folded substrates could be translocated via this system. Fusions of L. pneumophila Icm/ Dot-translocated substrates (IDTS) to dihydrofolate reductase (DHFR) or ubiquitin (Ub), small proteins known to fold rapidly, resulted in proteins with low translocation efficiencies. The folded moieties did not cause increased aggregation of the IDTS and did not impede interaction with the adaptor protein complex IcmS/IcmW, which is thought to form a soluble complex that promotes translocation. The translocation defect was alleviated with a Ub moiety harboring mutations known to destabilize its structure, indicating that unfolded proteins are preferred substrates. Real-time analysis of translocation, following movement during the first 30 min after bacterial contact with host cells, revealed that the folded moiety caused a kinetic defect in IDTS translocation. Expression of an IDTS fused to a folded moiety interfered with the translocation of other IDTS, consistent with it causing a blockage of the translocation channel. Furthermore, the folded protein fusions also interfered with intracellular growth, consistent with inefficient or impaired translocation of proteins critical for L. pneumophila intracellular growth. These studies indicate that substrates of the Icm/Dot T4SS are translocated to the host cytosol in an unfolded conformation and that folded proteins are stalled within the translocation channel, impairing the function of the secretion system.

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confidence: 99%

Poison Domains Block Transit of Translocated Substrates via the Legionella pneumophila Icm/Dot System

2013

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“…However, genes encoding secreted effectors were either induced or repressed by CpxR, which might indicate that different effectors are produced at different times during infection. 105 Despite all of this, a cpxR null mutation did not affect L. pneumophila survival inside macrophages. 104 This could be due to redundancy between CpxR-regulated and non-regulated effectors, or because the CpxR-activated effectors are only important in non-human hosts.…”

Section: Regulation Of Pili By the Cpx Responsementioning

confidence: 98%

“…104 A later study found that other genes encoding several Icm/Dot components and secreted effectors are also regulated by direct CpxR-DNA binding. 105 CpxR induced the genes encoding T4SS structural components. However, genes encoding secreted effectors were either induced or repressed by CpxR, which might indicate that different effectors are produced at different times during infection.…”

Section: Regulation Of Pili By the Cpx Responsementioning

confidence: 98%

“…104 This could be due to redundancy between CpxR-regulated and non-regulated effectors, or because the CpxR-activated effectors are only important in non-human hosts. 105 It is more difficult to explain why reduced expression of genes encoding T4SS structural components would not affect intracellular growth. One possibility is that there might be compensatory control by other regulators inside macrophages.…”

Section: Regulation Of Pili By the Cpx Responsementioning

confidence: 99%

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Regulation of bacterial virulence gene expression by cell envelope stress responses

Flores-Kim

Darwin

2014

Virulence

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“…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). Since activation of the Cpx response leads to inhibition of virulence determinant expression in many pathogens (53,(62)(63)(64), we performed our experiments in AKI medium, using conditions previously shown to maximize virulence factor production (49). A total of 174 genes were differentially regulated (i.e., at least a 2-fold increase or decrease in expression) upon transient overexpression of cpxR.…”

Section: Cholerae Cpxr Regulonmentioning

confidence: 99%

The Vibrio cholerae Cpx Envelope Stress Response Senses and Mediates Adaptation to Low Iron

2014

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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...

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The Response Regulator CpxR Directly Regulates Expression of SeveralLegionella pneumophila icm/dotComponents as Well as New Translocated Substrates

Cited by 101 publications

References 64 publications

Poison Domains Block Transit of Translocated Substrates via the Legionella pneumophila Icm/Dot System

Poison Domains Block Transit of Translocated Substrates via the Legionella pneumophila Icm/Dot System

Regulation of bacterial virulence gene expression by cell envelope stress responses

The Vibrio cholerae Cpx Envelope Stress Response Senses and Mediates Adaptation to Low Iron

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