Human SCCA serpins inhibit staphylococcal cysteine proteases by forming classic "serpin-like" covalent complexes

Proteolytic enzymes secreted by Staphylococcus aureus are considered important virulence factors. Here, we present data showing that staphylococci-derived cysteine proteases (staphopains) are efficiently inhibited by squamous cell carcinoma antigen 1 (SCCA1), a serpin abundant on the epithelial surfaces. The high association rate constant (k(ass)) for inhibitory complex formation (1.9 × 10⁴ and 5.8 ×10⁴ M⁻¹ s⁻¹ for staphopain A and staphopain B interaction with SCCA1, respectively) argues that SCCA1 can restrain staphopain activity in vivo at epithelial sites colonized by S. aureus. The mechanism of staphopain inhibition by SCCA1 is apparently the same as for serpin interaction with target serine proteases. The formation of a covalent complex results in cleavage of the SCCA1 reactive site peptide bond, and it is associated with the release of the C-terminal peptide of 37 amino acid residues from the serpin. Significantly, the SCCA1 reactive site closely resembles a motif in the reactive site loop of natural S. aureus-derived inhibitors of the staphopains (staphostatins). Taking into account that SCCA1 is predominantly expressed in epithelial tissues, including respiratory pathways, hair follicles and skin [Kato, H. (1996). Expression and function of squamous cell carcinoma antigen. Anticancer Res.16, 2149-2153.], all of which are regularly colonized by S. aureus, the physiological relevance of SCCA1-staphopain B interaction as a defense mechanism seems to be very well substantiated.