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Target-gene mediated activation of phosphatase activity of sensor kinase in the SaeRS two-component system of Staphylococcus aureus

ABSTRACT: In bacterial two-component regulatory systems (TCSs), dephosphorylation of phosphorylated response regulator is essential for resetting the activated systems to the pre-activation state. However, in the SaeRS TCS, a major virulence TCS of Staphylococcus aureus, the mechanism for dephosphorylation of the response regulator SaeR has not been identified. Here we report that two auxiliary proteins from the sae operon, SaeP and SaeQ, form a ternary complex with the sensor kinase SaeS and activate the sensor kinase’s phosphatase activity. Efficient activation of the phosphatase activity of SaeS required the presence of both SaeP and SaeQ. When SaeP and SaeQ were expressed, the expression of coagulase, a sae target with low affinity to phosphorylated SaeR, was greatly reduced, while the expression of alpha-hemolysin, a sae target with high affinity to phosphorylated SaeR, was not, demonstrating a differential effect of SaePQ on sae target gene expression. When expression of SaePQ was abolished, most sae target genes were induced at an elevated level. Since the expression of SaeP and SaeQ is induced by SaeRS TCS, these results suggest that the SaeRS TCS returns to pre-activation state by a negative feedback mechanism.

ORGANISM(S): Staphylococcus aureus subsp. aureus USA300 Staphylococcus aureus

PROVIDER: GSE36230 | GEO | 2012/03/09

SECONDARY ACCESSION(S): PRJNA153139

REPOSITORIES: GEO

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Target-gene mediated activation of phosphatase activity of sensor kinase in the SaeRS two-component system of Staphylococcus aureus

Project description:In bacterial two-component regulatory systems (TCSs), dephosphorylation of phosphorylated response regulator is essential for resetting the activated systems to the pre-activation state. However, in the SaeRS TCS, a major virulence TCS of Staphylococcus aureus, the mechanism for dephosphorylation of the response regulator SaeR has not been identified. Here we report that two auxiliary proteins from the sae operon, SaeP and SaeQ, form a ternary complex with the sensor kinase SaeS and activate the sensor kinase’s phosphatase activity. Efficient activation of the phosphatase activity of SaeS required the presence of both SaeP and SaeQ. When SaeP and SaeQ were expressed, the expression of coagulase, a sae target with low affinity to phosphorylated SaeR, was greatly reduced, while the expression of alpha-hemolysin, a sae target with high affinity to phosphorylated SaeR, was not, demonstrating a differential effect of SaePQ on sae target gene expression. When expression of SaePQ was abolished, most sae target genes were induced at an elevated level. Since the expression of SaeP and SaeQ is induced by SaeRS TCS, these results suggest that the SaeRS TCS returns to pre-activation state by a negative feedback mechanism. To examine the global effect of SaePQ on sae target gene expression, we treated the wild type strain of USA300-P23 and its P1 promoter mutant with HNP-1 and analyzed the transcription of sae target genes by microarray assays. WT and P1 cells were compared against a each other at the same time point and against a T=0 reference.

2012-03-09 | E-GEOD-36230 | biostudies-arrayexpress

The novel peptide ScrA acts through the SaeRS two component system to regulate virulence gene expression in Staphylococcus aureus

Project description:Staphylococcus aureus is a Gram-positive opportunistic pathogen, which is carried by approximately 30 % of the population at any time. In addition to being a commensal S. aureus can cause an array of infections, ranging from mild skin and soft tissue infections to life threatening endocarditis and septicemia. S. aureus encodes a variety of virulence factors that facilitate its pathogenic lifestyle. Genes encoding these virulence factors are under tight control by a complex regulatory network, which includes, sigma factors, sRNAs, and protein-based systems, such as Two-Component Systems (TCS). Previous work in our lab demonstrated that overexpression of the sRNA tsr37 leads to an increase in cellular aggregation in the absence of host serum. We determined that the clumping phenotype was dependent on a previously unannotated 88 amino acid protein encoded within the tsr37 sRNA transcript (which we named ScrA for S. aureus clumping regulator A). In addition to increased clumping, overexpression of ScrA also leads to increased biofilm formation. To investigate the mechanism of action of ScrA we performed mass spectrometry proteomics and RNA-sequencing in the ScrA overexpressing strain. A variety of virulence factors, including several surface adhesins were upregulated while several proteases were downregulated. Moreover, results showed a significant upregulation of the SaeRS two component system, suggesting that ScrA is influencing SaeRS activity. We go on to demonstrate that overexpression of ScrA in a saeR mutant abrogates the clumping/biofilm phenotypes confirming that ScrA functions via the Sae system. Finally, we identified the ArlRS TCS as a potential positive regulator of scrA expression. Collectively our results show that ScrA is an activator of the SaeRS system and suggests that ScrA may act as an intermediary between the ArlRS and SaeRS systems.

2022-08-11 | PXD028409 | Pride

SaeRS-dependent inhibition of biofilm formation in Staphylococcus aureus Newman

Project description:The SaeRS two-component regulatory system of Staphylococcus aureus is known to affect the expression of many genes. The SaeS protein is the histidine kinase responsible for phosphorylation of the response regulator SaeR. In S. aureus Newman, the sae system is constitutively expressed due to a point mutation in saeS, relative to other S. aureus strains, which results in substitution of proline for leucine at amino acid 18. Strain Newman is unable to form a robust biofilm and we report here that the biofilm-deficient phenotype is due to the saeSP allele. Replacement of the Newman saeSP with saeSL, or deletion of saeRS, resulted in a biofilm-proficient phenotype. Newman culture supernatants were observed to inhibit biofilm formation by other S. aureus strains, but did not affect biofilm formation by S. epidermidis. Culture supernatants of Newman saeSL or Newman ΔsaeRS had no significant effect on biofilm formation. The inhibitory factor was inactivated by incubation with proteinase K, but survived heating, indicating that the inhibitory protein is heat-stable. The inhibitory protein was found to affect the attachment step in biofilm formation, but had no effect on preformed biofilms. Replacement of saeSL with saeSP in the biofilm-proficient S. aureus USA300 FPR3757 resulted in the loss of biofilm formation. Culture supernatants of USA300 FPR3757 saeSP, did not inhibit biofilm formation by other staphylococci, suggesting that the inhibitory factor is produced but not secreted in the mutant strain. A number of biochemical methods were utilized to isolate the inhibitory protein. Although a number of candidate proteins were identified, none were found to be the actual inhibitor. In an effort to reduce the number of potential inhibitory genes, RNA-Seq analyses were done with wild-type strain Newman and the saeSL and ΔsaeRS mutants. RNA-Seq results indicated that sae regulates many genes that may affect biofilm formation by Newman.

2015-04-30 | GSE65827 | GEO

The novel peptide ScrA acts through the SaeRS two component system to regulate virulence gene expression in Staphylococcus aureus

2021-10-01 | GSE184753 | GEO

Role of the SaeRS two-component regulatory system in Staphylococcus epidermidis autolysis and biofilm formation

Project description:Background: Staphylococcus epidermidis (SE) has emerged as one of the most important causes of nosocomial infections. The SaeRS two-component signal transduction system (TCS) influences virulence and biofilm formation in Staphylococcus aureus. The deletion of saeR in S. epidermidis results in impaired anaerobic growth and decreased nitrate utilization. However, the regulatory function of SaeRS on biofilm formation and autolysis in S. epidermidis remains unclear. Results: The saeRS genes of SE1457 were deleted by homologous recombination. The saeRS deletion mutant, SE1457DsaeRS, exhibited increased biofilm formation that was disturbed more severely (a 4-fold reduction) by DNase I treatment compared to SE1457 and the complementation strain SE1457saec. Compared to SE1457 and SE1457saec, SE1457DsaeRS showed increased Triton X-100-induced autolysis (approximately 3-fold) and decreased cell viability in planktonic/biofilm states; further, SE1457DsaeRS also released more extracellular DNA (eDNA) in the biofilms. Correlated with the increased autolysis phenotype, the transcription of autolysis-related genes, such as atlE and aae, was increased in SE1457DsaeRS. Whereas the expression of accumulation-associated protein was up-regulated by 1.8-fold in 1457DsaeRS, the expression of an N-acetylglucosaminyl transferase enzyme (encoded by icaA) critical for polysaccharide intercellular adhesion (PIA) synthesis was not affected by the deletion of saeRS. Conclusions: Deletion of saeRS in S. epidermidis resulted in an increase in biofilm-forming ability, which was associated with increased eDNA release and up-regulated Aap expression. The increased eDNA release from SE1457DsaeRS was associated with increased bacterial autolysis and decreased bacterial cell viability in the planktonic/biofilm states. Comparision between SE1457 wild type strain and SA1457 SaeRS mutant strain after 4 hours and 12 hours of growth

2012-01-12 | E-GEOD-29309 | biostudies-arrayexpress

Role of the SaeRS two-component regulatory system in Staphylococcus epidermidis autolysis and biofilm formation

2012-01-12 | GSE29309 | GEO

Signal-independent activation reveals two-component regulatory networks.

Project description:Each bacterial species has specific regulatory systems to control physiology, adaptation, and host interactions. One challenge posed by this diversity is to define the evolving gene regulatory networks. This study aims to characterise two-component systems (TCS) in Streptococcus gagalactiae, the main cause of neonatal meningitis. Here we demonstrate signal-independent activation of signalling pathways by systematically targeting the conserved mechanism of phosphatase activity of the histidine kinases of the two main TCS families. Transcriptomic analysis resolves most pathways with high resolution, encompassing specialized, connected, and global regulatory systems. The activated network notably reveals the connection between CovRS and SaeRS signaling through the adhesin PbsP, linking the main regulators of host interactions to balance pathogenicity. Additionally, constitutive activation of the BceRS system reveals its role in cell envelope homeostasis beyond antimicrobial resistance. Overall, this study demonstrates the generalizability and versatility of TCS genetic activation to uncover regulatory logics and biological processes.

2024-03-25 | GSE261394 | GEO

Staphylococcus aureus subsp. aureus USA300

Project description:Target-gene mediated activation of phosphatase activity of sensor kinase in the SaeRS two-component system of Staphylococcus aureus

| PRJNA153139 | ENA

A vaginal tract signal detected by the GBS SaeRS system elicits transcriptomic changes and enhances murine colonization.

Project description:Streptococcus agalactiae (Group B Streptococcus, GBS) can colonize the human vaginal tract leading to both superficial and serious infections in adults and neonates. To study bacterial colonization of the reproductive tract in a mammalian system, we employed a murine vaginal carriage model. Using RNASeq, the transcriptome of GBS growing in vivo during vaginal carriage was determined. Over one-quarter of the genes in GBS were found to be differentially regulated during in vivo colonization as compared to laboratory cultures. A two-component system (TCS) homologous to the staphylococcal virulence regulator SaeRS was identified as being up-regulated in vivo. One of the SaeRS targets, pbsP, a proposed GBS vaccine candidate, was shown to be important for colonization of the vaginal tract. A component of vaginal lavage fluid acted as a signal to turn on pbsP expression via SaeRS. These data demonstrate the ability to quantify RNA expression directly from the murine vaginal tract and identify novel genes involved in vaginal colonization by GBS. They also provide more information about the regulation of an important virulence and colonization factor of GBS, pbsP, by the TCS SaeRS.

2018-02-06 | GSE109680 | GEO

The SaeRS two-component system dynamically regulates cellular adhesion and invasion during group B Streptococcus infection

Project description:Group B Streptococcus (GBS) is a pathobiont responsible for invasive infections in neonates and in the elderly. The transition from a commensal to an invasive pathogen relies on the timely regulation of a set of virulence factors. In this study, we characterized the role of the SaeRS two-component system in GBS pathogenesis. Loss-of-function mutations in the SaeR response regulator decrease virulence in mouse models of invasive infection . Transcriptome and in vivo analysis reveal a regulatory system specifically activated during infection to control the expression of only two virulence factors: the PbsP adhesin and the BvaP secreted protein. The in vivo surge in SaeRS-regulated genes is complemented by fine-tuning mediated by the repressor of virulence CovRS system to establish a coordinated response. Constitutive activation of the SaeRS regulatory pathway increases adhesion and invasion of epithelial and endothelial barriers, though at the cost of reduced virulence. In conclusion, SaeRS is a specialized and dynamic system that balances the invasion of host barriers with disease progression.

2024-07-10 | GSE269249 | GEO

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