Transcriptional Control of the Antimicrobial Peptide Resistance ugtL Gene by the Salmonella PhoP and SlyA Regulatory Proteins

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111

122

The sigma factor RpoS regulates the expression of many stress response genes and is required for virulence in several bacterial species. We now report that RpoS accumulates when Salmonella enterica serovar Typhimurium is growing logarithmically in media with low Mg 2؉ concentrations. This process requires the twocomponent regulatory system PhoP͞PhoQ, which is specifically activated in low Mg 2؉ . We show that PhoP controls RpoS protein turnover by serving as a transcriptional activator of the iraP (yaiB) gene, which encodes a product that enhances RpoS stability by interacting with RssB, the protein that normally delivers RpoS to the ClpXP protease for degradation. Mutation of the phoP gene rendered Salmonella as sensitive to hydrogen peroxide as an rpoS mutant after growth in low Mg 2؉ . In Escherichia coli, low Mg 2؉ leads to only modest RpoS stabilization, and iraP is not regulated by PhoP͞PhoQ. These findings add the sigma factor RpoS to the regulatory proteins and two-component systems that are elevated in a PhoP͞PhoQ-dependent fashion when Salmonella face low Mg 2؉ environments. Our data also exemplify the critical differences in regulatory circuits that exist between the closely related enteric bacteria Salmonella and E. coli.IraP ͉ magnesium ͉ Escherichia coli

Section: Discussionsupporting

confidence: 73%

The PhoP/PhoQ two-component system stabilizes the alternative sigma factor RpoS in Salmonella enterica

Latifi²,

Bougdour³

et al. 2006

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111

122

“…We began by investigating Yersinia's ability to promote transcription of the S. enterica mgtA and ugtL genes, which have no orthologs in Y. pestis and harbor distinct promoter architectures (Fig. 1A) (21)(22)(23). Y. pestis produced fluorescence levels similar to those of S. enterica when transcription of a promoterless gfp gene was driven by the promoter of the mgtA gene (Fig.…”

Section: Differential Ability Of the Yersinia Phop Protein To Expressmentioning

confidence: 99%

“…The upper band in H-I corresponds to treR, a PhoP-repressed transcript going in the reverse orientation (22). The upper band in K and L corresponds to a spurious transcript observed in vitro but not in vivo (21,45). Quantification of the in vitro transcription assays is shown in J for mgtA and in M for ugtL.…”

Section: Differential Ability Of the Yersinia Phop Protein To Expressmentioning

confidence: 99%

Transcription factor function and promoter architecture govern the evolution of bacterial regulons

Pérez

Groisman

2009

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Evolutionary changes in ancestral regulatory circuits can bring about phenotypic differences between related organisms. Studies of regulatory circuits in eukaryotes suggest that these modifications result primarily from changes in cis-regulatory elements (as opposed to alterations in the transcription factors that act upon these sequences). It is presently unclear how the evolution of gene regulatory circuits has proceeded in bacteria, given the rampant effects of horizontal gene transfer, which has significantly altered the composition of bacterial regulons. We now demonstrate that the evolution of the regulons governed by the regulatory protein PhoP in the related human pathogens Salmonella enterica and Yersinia pestis has entailed functional changes in the PhoP protein as well as in the architecture of PhoP-dependent promoters. These changes have resulted in orthologous PhoP proteins that differ both in their ability to promote transcription and in their role as virulence regulators. We posit that these changes allow bacterial transcription factors to incorporate newly acquired genes into ancestral regulatory circuits and yet retain control of the core members of a regulon.cis-regulatory elements ͉ horizontal gene transfer ͉ PhoP ͉ Salmonella ͉ Yersinia

“…In Salmonella enterica serovar Typhimurium, this transcriptional regulator modulates the intracellular expression of genes required for growth in macrophages (1) as well as bacterial resistance to cationic antimicrobial peptides (2,3) and to oxidative stress (4). Transcription of the slyA locus is activated by the PhoP/PhoQ 2-component system (2,5), which responds to different environmental signals including low-Mg 2ϩ , host-derived antimicrobial peptides, and acidic pH (6)(7)(8). Consistently, results from different laboratories showed that SlyA regulates a subset of PhoP-dependent genes, including ugtL and pagC, in Salmonella (2,3,(9)(10)(11).…”

mentioning

confidence: 99%

“…Transcription of the slyA locus is activated by the PhoP/PhoQ 2-component system (2,5), which responds to different environmental signals including low-Mg 2ϩ , host-derived antimicrobial peptides, and acidic pH (6)(7)(8). Consistently, results from different laboratories showed that SlyA regulates a subset of PhoP-dependent genes, including ugtL and pagC, in Salmonella (2,3,(9)(10)(11). To activate transcription of ugtL, both PhoP and SlyA must bind to its promoter simultaneously (2).…”

mentioning

confidence: 99%

A dual-signal regulatory circuit activates transcription of a set of divergent operons in Salmonella typhimurium

Zhao¹,

Weatherspoon²,

Kong

et al. 2008

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We present a molecular mechanism for signal transduction that activates transcription of the SlyA regulon in Salmonella typhimurium. We demonstrate that SlyA mediates transcriptional activation in response to guanosine tetraphosphate, ppGpp, according to the following observations: (i) in vivo transcription of SlyAdependent genes is repressed when ppGpp is absent; this transcription can be restored by overproducing SlyA; (ii) in vivo dimerization and binding of SlyA to the target promoter are facilitated in the presence of ppGpp; and (iii) in vitro SlyA binding to the target promoter is enhanced when ppGpp is supplemented. Thus, ppGpp must be the cytoplasmic component that stimulates SlyA regulatory function by interacting directly with this regulator in Salmonella. This signaling domain, integrated by the PhoP/PhoQ 2-component system that activates slyA transcription by sensing Mg 2؉ , forms feedforward loops that regulate chromosomal loci identified through a motif search over the S. typhimurium genome. Many such loci are divergent operons, each formed by 2 neighboring genes in which transcription of these 2 loci proceeds in opposite directions. Both genes, however, are controlled by PhoP and SlyA through a single shared PhoP box and SlyA box present in their intergenic regions. A substitution in either box sequence causes a simultaneous cessation of transcription of a divergent operon, pagD-pagC, equivalent to the phenotype in a phoP or slyA mutant. We also identified several chromosomal loci that possess pagCtype genes without the cognate pagD-type genes. Therefore, our results provide a molecular basis for the understanding of SlyAdependent phenotypes associated with Salmonella virulence.feedforward loop ͉ ppGpp ͉ SlyA ͉ divergent operon ͉ PhoP/PhoQ system