title: Inhibition of Staphylococcus aureus cysteine proteases by human serpin potentially limits staphylococcal virulence.
abstract: Bacterial proteases are considered virulence factors and it is presumed that by abrogating their activity, host endogenous protease inhibitors play a role in host defense against invading pathogens. Here we present data showing that Staphylococcus aureus cysteine proteases (staphopains) are efficiently inhibited by Squamous Cell Carcinoma Antigen 1 (SCCA1), an epithelial-derived serpin. The high association rate constant (k(ass)) for inhibitory complex formation (1.9×10(4) m/s and 5.8×10(4) m/s for staphopain A and staphopain B interaction with SCCA1, respectively), strongly suggests that SCCA1 can regulate staphopain activity in vivo at epithelial surfaces infected/colonized by S. aureus. The mechanism of staphopain inhibition by SCCA1 is apparently the same for serpin interaction with target serine proteases whereby the formation of a covalent complex result in cleavage of the inhibitory reactive site peptide bond and associated release of the C-terminal serpin fragment. Interestingly, the SCCA1 reactive site closely resembles a motif in the reactive site loop of native S. aureus-derived inhibitors of the staphopains (staphostatins). Given that S. aureus is a major pathogen of epithelial surfaces, we suggest that SCCA1 functions to temper the virulence of this bacterium by inhibiting the staphopains.
authors.affiliation: Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kantyka
authors.forename: Karolina
authors.initials: K
authors.lastname: Plaza
authors.forename: Joanna
authors.initials: J
authors.lastname: Koziel
authors.forename: Danuta
authors.initials: D
authors.lastname: Florczyk
authors.forename: Hennig R
authors.initials: HR
authors.lastname: Stennicke
authors.forename: Ida B
authors.initials: IB
authors.lastname: Thogersen
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Enghild
authors.forename: Gary A
authors.initials: GA
authors.lastname: Silverman
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Pak
authors.forename: Jan
authors.initials: J
authors.lastname: Potempa
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D011485:Protein Binding; D015843:Serpins / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000951:Antigens, Neoplasm; D015843:Serpins; C051072:squamous cell carcinoma-related antigen; D003546:Cysteine Endopeptidases; C501295:staphopain A protein, Staphylococcus aureus; C479137:staphopain B protein, Staphylococcus aureus