The SarA protein family of Staphylococcus aureus

Cheung, Ambrose L.; Nishina, Koren; Trotonda, María Pilar; Tamber, Sandeep

doi:10.1016/j.biocel.2007.10.032

Cited by 170 publications

(188 citation statements)

References 22 publications

(46 reference statements)

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“…S. aureus, a major human pathogen that is the most common source of bacterial infections in the community and hospital, causes a wide variety of diseases, ranging from minor skin infections to life-threatening blood infections (28). The virulence of this organism is controlled by regulatory networks composed of a large array of regulatory proteins, such as the agr system and the staphylococcal accessary protein A (SarA)/ MarR family global transcriptional regulator A (MgrA) family global regulatory proteins, which can respond to changing host microenvironments (29,30). Recent studies have revealed that the sole and conserved Cys residue in SarA, MgrA, and SarZ ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Protein cysteine phosphorylation of SarA/MgrA family transcriptional regulators mediates bacterial virulence and antibiotic resistance

Sun

Ding

et al. 2012

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

158

170

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Protein posttranslational modifications (PTMs), particularly phosphorylation, dramatically expand the complexity of cellular regulatory networks. Although cysteine (Cys) in various proteins can be subject to multiple PTMs, its phosphorylation was previously considered a rare PTM with almost no regulatory role assigned. We report here that phosphorylation occurs to a reactive cysteine residue conserved in the staphylococcal accessary regulator A (SarA)/MarR family global transcriptional regulator A (MgrA) family of proteins, and is mediated by the eukaryotic-like kinase-phosphatase pair Stk1-Stp1 in Staphylococcus aureus. Cys-phosphorylation is crucial in regulating virulence determinant production and bacterial resistance to vancomycin. Cell wall-targeting antibiotics, such as vancomycin and ceftriaxone, inhibit the kinase activity of Stk1 and lead to decreased Cys-phosphorylation of SarA and MgrA. An in vivo mouse model of infection established that the absence of stp1, which results in elevated protein Cys-phosphorylation, significantly reduces staphylococcal virulence. Our data indicate that Cys-phosphorylation is a unique PTM that can play crucial roles in bacterial signaling and regulation.

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Section: Resultsmentioning

confidence: 99%

Protein cysteine phosphorylation of SarA/MgrA family transcriptional regulators mediates bacterial virulence and antibiotic resistance

Sun

Ding

et al. 2012

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

158

170

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“…While there is no question that SarA is required for virulence determinant regulation, the mechanism by which SarA manifests its regulatory effects remains to be settled (36,64,138,186,217). Compounding the difficulty in defining SarA's mechanism of action is the fact that SarA represents one member of the SarA family of proteins, which consists of at least 11 members (34).…”

Section: Overview Of Staphylococcal Virulence Factor Regulationmentioning

confidence: 99%

At the Crossroads of Bacterial Metabolism and Virulence Factor Synthesis in Staphylococci

Somerville

Proctor

2009

Microbiol Mol Biol Rev

327

348

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SUMMARY Bacteria live in environments that are subject to rapid changes in the availability of the nutrients that are necessary to provide energy and biosynthetic intermediates for the synthesis of macromolecules. Consequently, bacterial survival depends on the ability of bacteria to regulate the expression of genes coding for enzymes required for growth in the altered environment. In pathogenic bacteria, adaptation to an altered environment often includes activating the transcription of virulence genes; hence, many virulence genes are regulated by environmental and nutritional signals. Consistent with this observation, the regulation of most, if not all, virulence determinants in staphylococci is mediated by environmental and nutritional signals. Some of these external signals can be directly transduced into a regulatory response by two-component regulators such as SrrAB; however, other external signals require transduction into intracellular signals. Many of the external environmental and nutritional signals that regulate virulence determinant expression can also alter bacterial metabolic status (e.g., iron limitation). Altering the metabolic status results in the transduction of external signals into intracellular metabolic signals that can be “sensed” by regulatory proteins (e.g., CodY, Rex, and GlnR). This review uses information derived primarily using Bacillus subtilis and Escherichia coli to articulate how gram-positive pathogens, with emphasis on Staphylococcus aureus and Staphylococcus epidermidis, regulate virulence determinant expression in response to a changing environment.

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“…The success of this bacterium in pathogenesis is largely owing to the sophisticated regulatory network composed of several global transcriptional regulators (e.g., SigB, Rot, MgrA, SarA, and SarA homologs) and 16 two-component systems (TCSs) (e.g., agr, srrAB, arlRS, vraRS, hssRS, and saeRS) (10)(11)(12), which enable the bacterium to rapidly sense and adapt to changing environment. Central to this regulatory network is the quorum-sensing agr system, which controls the expression of bacterial virulence in response to changes in cell density (10).…”

mentioning

confidence: 99%

Quorum-sensing agr mediates bacterial oxidation response via an intramolecular disulfide redox switch in the response regulator AgrA

Sun

Liang

Kong

et al. 2012

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

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Oxidation sensing and quorum sensing significantly affect bacterial physiology and host-pathogen interactions. However, little attention has been paid to the cross-talk between these two seemingly orthogonal signaling pathways. Here we show that the quorum-sensing agr system has a built-in oxidation-sensing mechanism through an intramolecular disulfide switch possessed by the DNA-binding domain of the response regulator AgrA. Biochemical and mass spectrometric analysis revealed that oxidation induces the intracellular disulfide bond formation between Cys-199 and Cys-228, thus leading to dissociation of AgrA from DNA. Molecular dynamics (MD) simulations suggest that the disulfide bond formation generates a steric clash responsible for the abolished DNA binding of the oxidized AgrA. Mutagenesis studies further established that Cys-199 is crucial for oxidation sensing. The oxidation-sensing role of Cys-199 is further supported by the observation that the mutant Staphylococcus aureus strain expressing AgrAC199S is more susceptible to H 2 O 2 owing to repression of the antioxidant bsaA gene under oxidative stress. Together, our results show that oxidation sensing is a component of the quorum-sensing agr signaling system, which serves as an intrinsic checkpoint to ameliorate the oxidation burden caused by intense metabolic activity and potential host immune response.

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The SarA protein family of Staphylococcus aureus

Cited by 170 publications

References 22 publications

Protein cysteine phosphorylation of SarA/MgrA family transcriptional regulators mediates bacterial virulence and antibiotic resistance

Protein cysteine phosphorylation of SarA/MgrA family transcriptional regulators mediates bacterial virulence and antibiotic resistance

At the Crossroads of Bacterial Metabolism and Virulence Factor Synthesis in Staphylococci

Quorum-sensing agr mediates bacterial oxidation response via an intramolecular disulfide redox switch in the response regulator AgrA

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