Prothrombin activation by a metalloprotease from Staphylococcus aureus

Węgrzynowicz, Z; Heczko, Piotr B; Drapeau, Gabriel R.; Jeljaszewicz, J.; Pulverer, G.

doi:10.1128/jcm.12.2.138-139.1980

Cited by 38 publications

(15 citation statements)

References 8 publications

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“…Finally, a number of the secreted proteases have been shown to cleave components of human blood, such as prothrombin and pro‐uPA, in order to facilitate survival and proliferation (Wegrzynowicz et al. ; Beaufort et al. ).…”

Section: Discussionmentioning

confidence: 99%

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Extracellular proteases are key mediators of Staphylococcus aureus virulence via the global modulation of virulence‐determinant stability

et al. 2012

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Staphylococcus aureus is a highly virulent and successful pathogen that causes a diverse array of diseases. Recently, an increase of severe infections in healthy subjects has been observed, caused by community-associated methicillin-resistant S. aureus (CA-MRSA). The reason for enhanced CA-MRSA virulence is unclear; however, work suggests that it results from hypersecretion of agr-regulated toxins, including secreted proteases. In this study, we explore the contribution of exo-proteases to CA-MRSA pathogenesis using a mutant lacking all 10 enzymes. We show that they are required for growth in peptide-rich environments, serum, in the presence of antimicrobial peptides (AMPs), and in human blood. We also reveal that extracellular proteases are important for resisting phagocytosis by human leukocytes. Using murine infection models, we reveal contrasting roles for the proteases in morbidity and mortality. Upon exo-protease deletion, we observed decreases in abscess formation, and impairment during organ invasion. In contrast, we observed hypervirulence of the protease-null strain in the context of mortality. This dichotomy is explained by proteomic analyses, which demonstrates exo-proteases to be key mediators of virulence-determinant stability. Specifically, increased abundance of both secreted (e.g. α-toxin, Psms, LukAB, LukE, PVL, Sbi, γ-hemolysin) and surface-associated (e.g. ClfA+B, FnbA+B, IsdA, Spa) proteins was observed upon protease deletion. Collectively, our findings provide a unique insight into the progression of CA-MRSA infections, and the role of secreted proteolytic enzymes.

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Section: Discussionmentioning

confidence: 99%

“…), fibrinogen, fibronectin, high‐molecular‐weight kinininigen, and plasminogen (Wegrzynowicz et al. ; Potempa et al. , ; Massimi et al.…”

Section: Discussionmentioning

confidence: 99%

Extracellular proteases are key mediators of Staphylococcus aureus virulence via the global modulation of virulence‐determinant stability

et al. 2012

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“…Both pathogenic bacteria and snake venom can release activators of coagulation that are at least partly responsible for tissue damage either at a site of infection or a snake bite. Most of these are classified as proteinases that activate prothrombin [7,8], factor X [9,10] or protein C [11,12]. In addition, factor IX activation by a proteinase in the venom from Russell's viper has also been described [13].…”

Section: Introductionmentioning

confidence: 99%

Activation of blood coagulation factor IX by gingipains R, arginine-specific cysteine proteinases from Porphyromonas gingivalis

et al. 2001

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The effect of two arginine-specific cysteine proteinases (gingipains R) from Porphyromonas gingivalis, an aetiological factor of adult periodontitis, on the activation of human factor IX was investigated in the presence of ethylene glycol, an activity enhancer of activated factor IX (factor IXa), with the use of a fluorogenic oligopeptide substrate. Each gingipain R rapidly activated factor IX but the 95 kDa proteinase complex (HRgpA) that contains both haemagglutinin/adhesion and catalytic domains was 2.4-fold more efficient than the single-chain 50 kDa gingipain R (RgpB), which has only a catalytic domain. SDS/PAGE and N-terminal sequence analysis of factor IX digestion fragments indicated that, like all endogenous activators, gingipains R also produce factor IXabeta via an IXa intermediate. Significantly, phospholipids augmented the activation of factor IX by HRgpA but not by RgpB in a Ca(2+)-dependent manner. In the presence of both cofactors the kinetic efficiency of HRgpA to activate factor IX (k(cat)/K(m)=1.9x10(6) M(-1).s(-1)) was 8.5-fold higher than that of RgpB (k(cat)/K(m)=2.3x10(5) M(-1).s(-1)) and double that of the factor VIIa-tissue factor complex, but 8-fold lower than that for factor XIa. A comparison of the relative activation rates of factor IX, factor X and prothrombin directly in plasma by HRgpA suggests a significant contribution for factor IX conversion in blood coagulation induced by gingipains R. Taken together, gingipains R are the first-reported activators of factor IX of bacterial origin. By this effect they could be involved in the production of thrombin as well as the subsequent generation of prostaglandins and interleukin 1, all of which have been found to be associated with the development and progression of periodontitis.

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“…Cysteine proteases (gingipains-R) produced by Porphyromonas gingivalis [11], and metalloproteases from Staphylococcus aureus [20] or Vibrio vulnificus [21], have been shown to activate human prothrombin. Metalloproteases from Serratia marcescens and Pseudomonas aeruginosa were reported to be capable of releasing thrombin activity from bovine prothrombin [22].…”

Section: Discussionmentioning

confidence: 99%

Activation of prothrombin by ASP, a serine protease released from Aeromonas sobria

Nitta¹,

Kobayashi²,

Irie³

et al. 2007

FEBS Letters

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The effect of a serine protease (ASP) secreted from Aeromonas sobria on plasma coagulation was investigated. Proteolytically active ASP promoted human plasma coagulation in a dose-dependent manner. Consistent with the preference for a factor Xa-specific oligo-peptide substrate, ASP produced enzymatic activity from human prothrombin but not from factors IX and X. ASP cleaved prothrombin to produce enzymatically active 37 kDa-fragment displaying the same molecular mass as a-thrombin. ASP is the first bacterial serine protease that produces a-thrombin, through which ASP may contribute to the induction of thrombotic tendency in disseminated intravascular coagulation complicated with sepsis caused by A. sobria infections.

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Prothrombin activation by a metalloprotease from Staphylococcus aureus

Cited by 38 publications

References 8 publications

Extracellular proteases are key mediators of Staphylococcus aureus virulence via the global modulation of virulence‐determinant stability

Extracellular proteases are key mediators of Staphylococcus aureus virulence via the global modulation of virulence‐determinant stability

Activation of blood coagulation factor IX by gingipains R, arginine-specific cysteine proteinases from Porphyromonas gingivalis

Activation of prothrombin by ASP, a serine protease released from Aeromonas sobria

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