Comparison of Staphopain A (ScpA) and B (SspB) precursor activation mechanisms reveals unique secretion kinetics of proSspB (Staphopain B), and a different interaction with its cognate Staphostatin, SspC

Nickerson, Nicholas N.; Ip, Jessica; Passos, Daniel Thompsen; McGavin, Martin J.

doi:10.1111/j.1365-2958.2009.06974.x

Cited by 37 publications

(31 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S1 in the supplemental material) (4,8). The other proteases are partly or fully autoactivated (4,(6)(7)(8), which supports the idea that SspB is the protease that cleaves galectin-3 in strain 8325-4. The Δaur strain supernatant still had a reduced level of cleavage of galectin-3, explained by inefficient SspB activation, as full activity of its activator, SspA, requires processing by Aur (8).…”

Section: Galectin-3 Cleavage By S Aureussupporting

confidence: 66%

Galectin-3 Is a Target for Proteases Involved in the Virulence of Staphylococcus aureus

Elmwall

Kwieciński

et al. 2017

Infect Immun

View full text Add to dashboard Cite

Staphylococcus aureus is a major cause of skin and soft tissue infection. The bacterium expresses four major proteases that are emerging as virulence factors: aureolysin (Aur), V8 protease (SspA), staphopain A (ScpA), and staphopain B (SspB). We hypothesized that human galectin-3, a ␤-galactoside-binding lectin involved in immune regulation and antimicrobial defense, is a target for these proteases and that proteolysis of galectin-3 is a novel immune evasion mechanism. Indeed, supernatants from laboratory strains and clinical isolates of S. aureus caused galectin-3 degradation. Similar proteolytic capacities were found in Staphylococcus epidermidis isolates but not in Staphylococcus saprophyticus. Galectin-3-induced activation of the neutrophil NADPH oxidase was abrogated by bacterium-derived proteolysis of galectin-3, and SspB was identified as the major protease responsible. The impact of galectin-3 and protease expression on S. aureus virulence was studied in a murine skin infection model. In galectin-3 ϩ/ϩ mice, SspB-expressing S. aureus caused larger lesions and resulted in higher bacterial loads than protease-lacking bacteria. No such difference in bacterial load or lesion size was detected in galectin-3 Ϫ/Ϫ mice, which overall showed smaller lesion sizes than the galectin-3 ϩ/ϩ animals. In conclusion, the staphylococcal protease SspB inactivates galectin-3, abrogating its stimulation of oxygen radical production in human neutrophils and increasing tissue damage during skin infection.

show abstract

Section: Galectin-3 Cleavage By S Aureussupporting

confidence: 66%

Galectin-3 Is a Target for Proteases Involved in the Virulence of Staphylococcus aureus

Elmwall

Kwieciński

et al. 2017

Infect Immun

View full text Add to dashboard Cite

show abstract

“…V8 has narrow substrate specificity, cutting specifically after glutamate residues (13), and the zymogen also has to be activated by Aur in order to be functional (16), both properties that limit the utility of V8 as a biofilm modulator. In contrast, the other major proteases (Aur, ScpA, SspB) have broader target specificity and both Aur and ScpA self-activate (14,15,59). ScpA in particular seems like an obvious candidate to control biofilm matrix structure.…”

Section: Discussionmentioning

confidence: 99%

“…1B). The Aur and ScpA zymogens autoactivate outside the cell (14,15), and SspA and SspB activation relies on a proteolytic cascade in which Aur processes SspA (16) and SspA subsequently processes SspB (17). There is preliminary evidence that the SspA (V8) serine protease might be important in biofilm remodeling (9,10,12), but the contribution of the other proteases is less clear.…”

mentioning

confidence: 99%

Staphopains Modulate Staphylococcus aureus Biofilm Integrity

et al. 2013

View full text Add to dashboard Cite

Staphylococcus aureus is a known cause of chronic biofilm infections that can reside on medical implants or host tissue. Recent studies have demonstrated an important role for proteinaceous material in the biofilm structure. The S. aureus genome encodes many secreted proteases, and there is growing evidence that these enzymes have self-cleavage properties that alter biofilm integrity. However, the specific contribution of each protease and mechanism of biofilm modulation is not clear. To address this issue, we utilized a sigma factor B (⌬sigB) mutant where protease activity results in a biofilm-negative phenotype, thereby creating a condition where the protease(s) responsible for the phenotype could be identified. Using a plasma-coated microtiter assay, biofilm formation was restored to the ⌬sigB mutant through the addition of the cysteine protease inhibitor E-64 or by using Staphostatin inhibitors that specifically target the extracellular cysteine proteases SspB and ScpA (called Staphopains). Through construction of gene deletion mutants, we determined that an sspB scpA double mutant restored ⌬sigB biofilm formation, and this recovery could be replicated in plasma-coated flow cell biofilms. Staphopain levels were also found to be decreased under biofilm-forming conditions, possibly allowing biofilm establishment. The treatment of S. aureus biofilms with purified SspB or ScpA enzyme inhibited their formation, and ScpA was also able to disperse an established biofilm. The antibiofilm properties of ScpA were conserved across S. aureus strain lineages. These findings suggest an underappreciated role of the SspB and ScpA cysteine proteases in modulating S. aureus biofilm architecture.

show abstract

“…Techniques for genetic manipulation of S. aureus were conducted according to established guidelines (32) and as described in our previous work (24,25,33). The University of Nebraska transposon mutant library (34) was used as a source of transposon insertions that inactivated SAUSA300_2490 (NE1393) and SAUS300_2489 (NE2336).…”

Section: Methodsmentioning

confidence: 99%

Inducible Expression of a Resistance-Nodulation-Division-Type Efflux Pump in Staphylococcus aureus Provides Resistance to Linoleic and Arachidonic Acids

et al. 2015

Self Cite

View full text Add to dashboard Cite

Although Staphylococcus aureus is exposed to antimicrobial fatty acids on the skin, in nasal secretions, and in abscesses, a specific mechanism of inducible resistance to this important facet of innate immunity has not been identified. Here, we have sequenced the genome of S. aureus USA300 variants selected for their ability to grow at an elevated concentration of linoleic acid. The fatty acid-resistant clone FAR7 had a single nucleotide polymorphism resulting in an H 121 Y substitution in an uncharacterized transcriptional regulator belonging to the AcrR family, which was divergently transcribed from a gene encoding a member of the resistance-nodulation-division superfamily of multidrug efflux pumps. We named these genes farR and farE, for regulator and effector of fatty acid resistance, respectively. Several lines of evidence indicated that FarE promotes efflux of antimicrobial fatty acids and is regulated by FarR. First, expression of farE was strongly induced by arachidonic and linoleic acids in an farRdependent manner. Second, an H 121 Y substitution in FarR resulted in increased expression of farE and was alone sufficient to promote increased resistance of S. aureus to linoleic acid. Third, inactivation of farE resulted in a significant reduction in the inducible resistance of S. aureus to the bactericidal activity of 100 M linoleic acid, increased accumulation of [ 14 C]linoleic acid by growing cells, and severely impaired growth in the presence of nonbactericidal concentrations of linoleic acid. Cumulatively, these findings represent the first description of a specific mechanism of inducible resistance to antimicrobial fatty acids in a Gram-positive pathogen. IMPORTANCEStaphylococcus aureus colonizes approximately 25% of humans and is a leading cause of human infectious morbidity and mortality. To persist on human hosts, S. aureus must have intrinsic defense mechanisms to cope with antimicrobial fatty acids, which comprise an important component of human innate defense mechanisms. We have identified a novel pair of genes, farR and farE, that constitute a dedicated regulator and effector of S. aureus resistance to linoleic and arachidonic acids, which are major fatty acids in human membrane phospholipid. Expression of farE, which encodes an efflux pump, is induced in an farRdependent mechanism, in response to these antimicrobial fatty acids that would be encountered in a tissue abscess. Staphylococcus aureus has a dichotomous relation with human hosts, being able to establish an asymptomatic commensal relationship, but is also historically known as a leading cause of human infectious morbidity and mortality. Significantly, death attributed to S. aureus in the United States is now comparable to mortality rates for AIDS, tuberculosis, and viral hepatitis (1-3). Not surprisingly, therefore, S. aureus has been the subject of intensive research on mechanisms of pathogenesis and acquisition and transfer of antibiotic resistance and of efforts to identify potential vaccine antigens (4-6). Until the late ...

show abstract

Comparison of Staphopain A (ScpA) and B (SspB) precursor activation mechanisms reveals unique secretion kinetics of proSspB (Staphopain B), and a different interaction with its cognate Staphostatin, SspC

Cited by 37 publications

References 70 publications

Galectin-3 Is a Target for Proteases Involved in the Virulence of Staphylococcus aureus

Galectin-3 Is a Target for Proteases Involved in the Virulence of Staphylococcus aureus

Staphopains Modulate Staphylococcus aureus Biofilm Integrity

Inducible Expression of a Resistance-Nodulation-Division-Type Efflux Pump in Staphylococcus aureus Provides Resistance to Linoleic and Arachidonic Acids

Contact Info

Product

Resources

About