A role for Trigger Factor and an Rgg-like regulator in the transcription, secretion and processing of the cysteine proteinase of<i>Streptococcus pyogenes</i>

Lyon, William R.; Gibson, Carmela M.; Caparon, Michael G.

doi:10.1093/emboj/17.21.6263

Cited by 242 publications

(360 citation statements)

References 79 publications

(94 reference statements)

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“…Finally, SpeB activity is governed, in part, by the protein RopA. RopA contributes to the posttranslational processing of SpeB that establishes an active conformation after secretion (32). Fluoride caused a marked decrease in the expression of RopA.…”

Section: Effect Of Fluoride On Protein Expression In S Pyogenes Cultmentioning

confidence: 99%

Fluoride Exposure Attenuates Expression of Streptococcus pyogenes Virulence Factors

Thongboonkerd¹,

Luengpailin²,

Cao³

et al. 2002

Journal of Biological Chemistry

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Fluoridation causes an obvious reduction of dental caries by interference with cariogenic streptococci. However, the effect of fluoride on group A streptococci that causes rheumatic fever and acute poststreptococcal glomerulonephritis is not known. We have used proteomic analysis to create a reference proteome map for Streptococcus pyogenes and to determine fluoride-induced protein changes in the streptococci. Cellular and extracellular proteins were resolved by two-dimensional polyacrylamide gel electrophoresis and identified by matrix-assisted laser desorption ionization mass spectrometry. 183 protein spots were visualized, and 74 spots representing 60 unique proteins were identified. A 16-h exposure to sodium fluoride caused decreased expression of proteins required to respond to cellular stress, including anti-oxidants, glycolytic enzymes, transcriptional and translational regulators, and protein folding. Fluoride caused decreased cellular expression of two well-characterized S. pyogenes virulence factors. Fluoride decreased expression of glyceraldehyde-3-phosphate dehydrogenase, which acts to bind fibronectin and promote bacterial adherence. We also performed proteomic analysis of protein released by S. pyogenes into the culture supernatant and observed decreased expression of M proteins following fluoride exposure. These data provide evidence that fluoride causes decreased expression by S. pyogenes proteins used to respond to stress, virulence factors, and implicated in nonsuppurative complications of S. pyogenes, including glomerulonephritis and rheumatic fever.The incidence of some sequelae of group A streptococcal infection such as rheumatic fever and acute post-streptococcal glomerulonephritis (APSGN) 1 has decreased over the last five decades in the United States and western countries (1-3). However, these disorders continue unabated and are important public health problems in developing countries (1,3,4). The effects of fluoride on cariogenic Streptococcus mutans and other bacteria have been extensively studied. Fluoride inhibits enolase, a glycolytic enzyme (5, 6), inhibits F-ATPase activity resulting in less acidurance (7,8), reduces glucan-binding lectin activity (9), and decreases glucose incorporation (10). However, the effects of fluoride on group A Streptococci have not been examined. To examine simultaneous changes in multiple virulence factors, we performed a proteomic analysis of S. pyogenes exposed to fluoride. Western blotting and other immunological methods have been successfully used to study protein expression of various microorganisms, cells, and tissues. However, these techniques are constrained by the limited number of proteins that can be studied in each experiment and the availability of specific antibodies. Proteomic techniques date to 1975, when two-dimensional PAGE was simultaneously described by O'Farrell and Klose (11, 12) and applied to the study of a large number of proteins simultaneously. In twodimensional PAGE proteins are separated by differential isoelectric point (pI)...

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Section: Effect Of Fluoride On Protein Expression In S Pyogenes Cultmentioning

confidence: 99%

Fluoride Exposure Attenuates Expression of Streptococcus pyogenes Virulence Factors

Thongboonkerd¹,

Luengpailin²,

Cao³

et al. 2002

Journal of Biological Chemistry

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“…The biogenesis of the active SpeB protease is tightly regulated at both transcriptional and post-translational levels [20]. speB expression is controlled by various transcriptional regulators, including the well-characterized regulator of protease B (RopB) [21–23]. RopB binds at direct and inverted repeats located upstream of the speB promoter to induce speB expression [23,24].…”

Section: Introductionmentioning

confidence: 99%

“…speB harbours a long 5′ UTR where two transcriptional start sites (TSSs), named P1 and P2, were originally predicted 697 nt and 137 nt upstream of the speB start codon, respectively [28]. Despite the important regulatory role of the intergenic region in speB expression, the annotation of this region is not consistent in the literature [21,23,26–29]. …”

Section: Introductionmentioning

confidence: 99%

RNase Y-mediated regulation of the streptococcal pyrogenic exotoxin B

et al. 2018

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Endoribonuclease Y (RNase Y) is a crucial regulator of virulence in Gram-positive bacteria. In the human pathogen Streptococcus pyogenes, RNase Y is required for the expression of the major secreted virulence factor streptococcal pyrogenic exotoxin B (SpeB), but the mechanism involved in this regulation remains elusive. Here, we demonstrate that the 5′ untranslated region of speB mRNA is processed by several RNases including RNase Y. In particular, we identify two RNase Y cleavage sites located downstream of a guanosine (G) residue. To assess whether this nucleotide is required for RNase Y activity in vivo, we mutated it and demonstrate that the presence of this G residue is essential for the processing of the speB mRNA 5′ UTR by RNase Y. Although RNase Y directly targets and processes speB, we show that RNase Y-mediated regulation of speB expression occurs primarily at the transcriptional level and independently of the processing in the speB mRNA 5′ UTR. To conclude, we demonstrate for the first time that RNase Y processing of an mRNA target requires the presence of a G. We also provide new insights on the speB 5′ UTR and on the role of RNase Y in speB regulation.

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“…Rgg2 Sp , Rgg3 Sp , and ComR Sp are transcription factors whose activity is regulated via interactions with pheromones (4,21,22). RopB is a transcription factor as well, and its role in pathogenesis has been thoroughly documented; however, the exact identity of RopB's cognate regulatory pheromone has not been determined (23)(24)(25). Thus far, there are two known families of Streptococcus peptide pheromones, the SigX-inducing peptides (XIPs) and the short hydrophobic peptides (SHPs).…”

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confidence: 99%

Rgg protein structure–function and inhibition by cyclic peptide compounds

Parashar

Aggarwal

Federle

et al. 2015

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

100

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Peptide pheromone cell-cell signaling (quorum sensing) regulates the expression of diverse developmental phenotypes (including virulence) in Firmicutes, which includes common human pathogens, e.g., Streptococcus pyogenes and Streptococcus pneumoniae. Cytoplasmic transcription factors known as "Rgg proteins" are peptide pheromone receptors ubiquitous in Firmicutes. Here we present X-ray crystal structures of a Streptococcus Rgg protein alone and in complex with a tight-binding signaling antagonist, the cyclic undecapeptide cyclosporin A. To our knowledge, these represent the first Rgg protein X-ray crystal structures. Based on the results of extensive structure-function analysis, we reveal the peptide pheromone-binding site and the mechanism by which cyclosporin A inhibits activation of the peptide pheromone receptor. Guided by the Rgg-cyclosporin A complex structure, we predicted that the nonimmunosuppressive cyclosporin A analog valspodar would inhibit Rgg activation. Indeed, we found that, like cyclosporin A, valspodar inhibits peptide pheromone activation of conserved Rgg proteins in medically relevant Streptococcus species. Finally, the crystal structures presented here revealed that the Rgg protein DNA-binding domains are covalently linked across their dimerization interface by a disulfide bond formed by a highly conserved cysteine. The DNA-binding domain dimerization interface observed in our structures is essentially identical to the interfaces previously described for other members of the XRE DNA-binding domain family, but the presence of an intermolecular disulfide bond buried in this interface appears to be unique. We hypothesize that this disulfide bond may, under the right conditions, affect Rgg monomer-dimer equilibrium, stabilize Rgg conformation, or serve as a redox-sensitive switch.

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A role for Trigger Factor and an Rgg-like regulator in the transcription, secretion and processing of the cysteine proteinase ofStreptococcus pyogenes

Cited by 242 publications

References 79 publications

Fluoride Exposure Attenuates Expression of Streptococcus pyogenes Virulence Factors

Fluoride Exposure Attenuates Expression of Streptococcus pyogenes Virulence Factors

RNase Y-mediated regulation of the streptococcal pyrogenic exotoxin B

Rgg protein structure–function and inhibition by cyclic peptide compounds

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