In the<i>Staphylococcus aureus</i>Two-Component System<i>sae</i>, the Response Regulator SaeR Binds to a Direct Repeat Sequence and DNA Binding Requires Phosphorylation by the Sensor Kinase SaeS

Sun, Fei; Li, Chunling; Jeong, Do‐Won; Sohn, Changmo; He, Chuan; Bae, Taeok

doi:10.1128/jb.01524-09

Cited by 106 publications

(186 citation statements)

References 51 publications

(70 reference statements)

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“…Although its activity is slightly autorepressed, the promoter is fairly constitutive, and the transcripts from the promoter are observed throughout growth phases (1,12). On the other hand, the P1 promoter has two SaeR binding sites and requires the SaeRS TCS for its transcriptional activity (autoinduction) (12,15,34,42). The P1 promoter activity is 2 to 30 times higher than that of the P3 promoter (12,26).…”

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Identification of the P3 Promoter and Distinct Roles of the Two Promoters of the SaeRS Two-Component System in Staphylococcus aureus

et al. 2011

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In Staphylococcus aureus, the SaeRS two-component system (TCS) encoded by the saePQRS operon controls expression of major virulence factors, such as coagulase and alpha-hemolysin. The saePQRS operon has two promoters: P1 and P3. The P1 promoter, a strong promoter, is autoinduced and can transcribe all four genes. Compared with P1, P3 shows fairly low but constitutive promoter activity, and it transcribes only saeR and saeS, the two genes encoding response regulator SaeR and sensor kinase SaeS. However, the role of each promoter in sae signaling has not been rigorously defined. In this study, we found that the genuine transcription start site (TSS) of P3 is located 78 nucleotides downstream of the previously reported TSS. Subsequently, the P3 promoter sequence was identified and validated by mutagenesis analyses. Deletion of the saePQ region including the P1 promoter did not significantly alter the expression patterns of coagulase and alpha-hemolysin, two well-known sae target genes. Due to its L18P substitution in a transmembrane domain, SaeS in strain Newman has a constitutive kinase activity. Interestingly, the mutation also rendered the protein unstable, but the protein stability was restored by SaeQ, suggesting a possible SaeQ-SaeS interaction. Ironically, the same mutation seems to increase mRNA stability. SaeR appears to be stabilized by SaeS, possibly by a proteinprotein interaction. Chromosomal mutation of P1 did not affect the expression pattern of coagulase and alpha-hemolysin. Based on these results, we conclude that transcription of saeRS from P3 is sufficient for target gene activation and that P1 is not involved in the activation.

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“…The genes saeR and saeS encode the RR and HK, respectively. SaeR recognizes the binding sequence GTTAAN 6 GTTAA (where N represents any nucleotide) and, for DNA binding, needs to be phosphorylated by SaeS (35,42). SaeS is a 351-aa polypeptide and is predicted to have two transmembrane helices at the N terminus.…”

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Identification of the P3 Promoter and Distinct Roles of the Two Promoters of the SaeRS Two-Component System in Staphylococcus aureus

et al. 2011

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“…SaeR binds to a consensus sequence within virulence factor promoters to induce gene expression (309,321). SaeR binding sites have been identified within the promoter regions of nearly all leucocidin genes, including lukSF, hlgA, hlgCB, lukED, and lukAB (lukHG) (309,321). Experimentally, an sae deletion mutant of S. aureus has significantly reduced transcript levels of all known leucocidins and is dramatically attenuated in murine infection models (308)(309)(310)315).…”

Section: Regulation At the Transcriptional Levelmentioning

confidence: 99%

“…7) (309, 315). SaeRS is a two-component system that responds to host environmental cues, including PMNs, to upregulate the expression of a diverse repertoire of S. aureus secreted proteins, many of which are major virulence factors (304,309,310,(316)(317)(318)(319)(320)(321). SaeR binds to a consensus sequence within virulence factor promoters to induce gene expression (309,321).…”

Section: Regulation At the Transcriptional Levelmentioning

confidence: 99%

The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus

Alonzo

Torres

2014

Microbiol Mol Biol Rev

239

290

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SUMMARY The ability to produce water-soluble proteins with the capacity to oligomerize and form pores within cellular lipid bilayers is a trait conserved among nearly all forms of life, including humans, single-celled eukaryotes, and numerous bacterial species. In bacteria, some of the most notable pore-forming molecules are protein toxins that interact with mammalian cell membranes to promote lysis, deliver effectors, and modulate cellular homeostasis. Of the bacterial species capable of producing pore-forming toxic molecules, the Gram-positive pathogen Staphylococcus aureus is one of the most notorious. S. aureus can produce seven different pore-forming protein toxins, all of which are believed to play a unique role in promoting the ability of the organism to cause disease in humans and other mammals. The most diverse of these pore-forming toxins, in terms of both functional activity and global representation within S. aureus clinical isolates, are the bicomponent leucocidins. From the first description of their activity on host immune cells over 100 years ago to the detailed investigations of their biochemical function today, the leucocidins remain at the forefront of S. aureus pathogenesis research initiatives. Study of their mode of action is of immediate interest in the realm of therapeutic agent design as well as for studies of bacterial pathogenesis. This review provides an updated perspective on our understanding of the S. aureus leucocidins and their function, specificity, and potential as therapeutic targets.

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“…SaeR, the response regulator, and SaeS, the sensor kinase, comprise the traditional machinery of the TCS (13). SaeR is a member of the OmpR family of response regulators and binds a direct DNA repeat sequence upon phosphorylation by SaeS to activate transcription of genes in the sae regulon (11,14). SaeS, a member of the HisKA family of histidine protein kinases, is predicted to contain a sensing domain composed of only two transmembrane segments connected by a short extracellular loop (15).…”

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Differential regulation of staphylococcal virulence by the sensor kinase SaeS in response to neutrophil-derived stimuli

Flack

Zurek

Meishery

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Two-component systems (TCSs) are highly conserved across bacteria and are used to rapidly sense and respond to changing environmental conditions. The human pathogen Staphylococcus aureus uses the S. aureus exoprotein expression (sae) TCS to sense host signals and activate transcription of virulence factors essential to pathogenesis. Despite its importance, the mechanism by which the histidine kinase SaeS recognizes specific host stimuli is unknown. After mutagenizing the predicted extracellular loop of SaeS, we discovered one methionine residue (M31) was essential for the ability of S. aureus to transcribe sae target genes, including hla, lukAB/lukGH, and hlgA. This single M31A mutation also significantly reduced cytotoxicity in human neutrophils to levels observed in cells following interaction with ΔsaeS. Another important discovery was that mutation of two aromatic anchor residues (W32A and F33A) disrupted the normal basal signaling of SaeS in the absence of inducing signals, yet both mutant kinases had appropriate activation of effector genes following exposure to neutrophils. Although the transcriptional profile of aromatic mutation W32A was consistent with that of WT in response to human α-defensin 1, mutant kinase F33A did not properly transcribe the γ-toxin genes in response to this stimulus. Taken together, our results provide molecular evidence for how SaeS recognizes host signals and triggers activation of select virulence factors to facilitate evasion of innate immunity. These findings have important implications for signal transduction in prokaryotes and eukaryotes due to conservation of aromatic anchor residues across both of these domains and the important role they play in sensor protein structure and function.host-pathogen interactions | membrane proteins

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In theStaphylococcus aureusTwo-Component Systemsae, the Response Regulator SaeR Binds to a Direct Repeat Sequence and DNA Binding Requires Phosphorylation by the Sensor Kinase SaeS

Cited by 106 publications

References 51 publications

Identification of the P3 Promoter and Distinct Roles of the Two Promoters of the SaeRS Two-Component System in Staphylococcus aureus

Identification of the P3 Promoter and Distinct Roles of the Two Promoters of the SaeRS Two-Component System in Staphylococcus aureus

The Bicomponent Pore-Forming Leucocidins of Staphylococcus aureus

Differential regulation of staphylococcal virulence by the sensor kinase SaeS in response to neutrophil-derived stimuli

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