From transcription to activation: how group A streptococcus, the flesh‐eating pathogen, regulates SpeB cysteine protease production

Carroll, Rachel; Musser, James M.

doi:10.1111/j.1365-2958.2011.07709.x

Cited by 70 publications

(87 citation statements)

References 72 publications

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“…4). speB expression was previously shown to be growth phase dependent and affected by nutritional and environmental conditions [20]. In accordance with those data, we observed an increase of speB mRNA abundance from EL to ES growth phases (Fig.…”

Section: Speb Mrna Abundance Is Downregulated In ∆Rnysupporting

confidence: 91%

“…SpeB is produced as an inactive zymogen, which undergoes maturation processes to become active. 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].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Speb Mrna Abundance Is Downregulated In ∆Rnysupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

RNase Y-mediated regulation of the streptococcal pyrogenic exotoxin B

et al. 2018

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“…In Streptococcus pyogenes, the activity of the secreted protease SpeB requires PPIase activity (9,36). To determine if S. aureus secreted protease activity similarly requires a PPIase, we examined the ability of the prsA, ppiB, and tig mutant strains to degrade casein on milk agar plates (Fig.…”

Section: Role Of S Aureus Ppiases In Nuclease Activitymentioning

confidence: 99%

An Intracellular Peptidyl-Prolyl cis / trans Isomerase Is Required for Folding and Activity of the Staphylococcus aureus Secreted Virulence Factor Nuclease

et al. 2017

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Staphylococcus aureus is an important human pathogen that relies on a large repertoire of secreted and cell wall-associated proteins for pathogenesis. Consequently, the ability of the organism to cause disease is absolutely dependent on its ability to synthesize and successfully secrete these proteins. In this study, we investigate the role of peptidyl-prolyl cis/trans isomerases (PPIases) on the activity of the S. aureus secreted virulence factor nuclease (Nuc). We identify a staphylococcal cyclophilin-type PPIase (PpiB) that is required for optimal activity of Nuc. Disruption of ppiB results in decreased nuclease activity in culture supernatants; however, the levels of Nuc protein are not altered, suggesting that the decrease in activity results from misfolding of Nuc in the absence of PpiB. We go on to demonstrate that PpiB exhibits PPIase activity in vitro, is localized to the bacterial cytosol, and directly interacts with Nuc in vitro to accelerate the rate of Nuc refolding. Finally, we demonstrate an additional role for PpiB in S. aureus hemolysis and demonstrate that the S. aureus parvulin-type PPIase PrsA also plays a role in the activity of secreted virulence factors. The deletion of prsA leads to a decrease in secreted protease and phospholipase activity, similar to that observed in other Gram-positive pathogens. Together, these results demonstrate, for the first time to our knowledge, that PPIases play an important role in the secretion of virulence factors in S. aureus.IMPORTANCE Staphylococcus aureus is a highly dangerous bacterial pathogen capable of causing a variety of infections throughout the human body. The ability of S. aureus to cause disease is largely due to an extensive repertoire of secreted and cell wall-associated proteins, including adhesins, toxins, exoenzymes, and superantigens. These virulence factors, once produced, are typically transported across the cell membrane by the secretory (Sec) system in a denatured state. Consequently, once outside the cell, they must refold into their active form. This step often requires the assistance of bacterial folding proteins, such as PPIases. In this work, we investigate the role of PPIases in S. aureus and uncover a cyclophilin-type enzyme that assists in the folding/refolding of staphylococcal nuclease.KEYWORDS cyclophilin, Nuc, PI-PLC, PPIase, parvulin, PpiB, PrsA, Staphylococcus aureus, nuclease, protease T he proline peptide bond is unique in nature in that both the cis and trans forms can occur in vivo, with the cis conformation existing approximately 6.5% of the time (1). In contrast, for all other naturally occurring amino acids, steric hindrance between side chains precludes the cis form and overwhelmingly favors the trans form (2). The presence of both the cis and trans forms of proline peptide bonds has important consequences for protein tertiary structure. In certain cases, the isomerization state of

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“…Leupeptin is an arginine-dependent protease inhibitor. Because Cys at position 192, His at position 340, and Trp at position 357 play critical roles in the enzymatic activity of SpeB (20), leupeptin might be less effective for inhibition of SpeB activity as compared with those other cysteine proteases. Consequently, we investigated whether SpeB is involved in cleavage of E-cadherin.…”

Section: Gas Supernatant Induces Cleavage Of E-cadherin-culturementioning

confidence: 99%

“…SpeB is secreted as a 42-kDa zymogen and autocatalyzed into an active 28-kDa cysteine protease (18,20), and its substrate specificity is similar to that of the papain family of proteases (21). Active SpeB cleaves the host extracellular matrix (22), immunoglobulins (23,24), and complement components (16).…”

Section: Gas Supernatant Induces Cleavage Of E-cadherin-culturementioning

confidence: 99%

Group A Streptococcal Cysteine Protease Cleaves Epithelial Junctions and Contributes to Bacterial Translocation

Sumitomo

Nakata

Higashino

et al. 2013

Journal of Biological Chemistry

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Background: Group A Streptococcus (GAS) translocates across the host epithelial barrier. Results: Streptococcal pyrogenic exotoxin B (SpeB) directly cleaves junctional proteins. Conclusion:The proteolytic efficacy of SpeB allows GAS to translocate across the epithelial barrier. Significance: SpeB-mediated dysfunction of the epithelial barrier may have important implications for not only bacterial invasion but also dissemination of other virulence factors throughout intercellular spaces.

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From transcription to activation: how group A streptococcus, the flesh‐eating pathogen, regulates SpeB cysteine protease production

Cited by 70 publications

References 72 publications

RNase Y-mediated regulation of the streptococcal pyrogenic exotoxin B

RNase Y-mediated regulation of the streptococcal pyrogenic exotoxin B

An Intracellular Peptidyl-Prolyl cis / trans Isomerase Is Required for Folding and Activity of the Staphylococcus aureus Secreted Virulence Factor Nuclease

Group A Streptococcal Cysteine Protease Cleaves Epithelial Junctions and Contributes to Bacterial Translocation

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