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Down-regulation of human extracellular cysteine protease inhibitors by the secreted staphylococcal cysteine proteases, staphopain A and B.

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Author

Summary, in English

Of seven human cystatins investigated, none inhibited the cysteine proteases staphopain A and B secreted by the human pathogen Staphylococcus aureus. Rather, the extracellular cystatins C, D and E/M were hydrolyzed by both staphopains. Based on MALDI-TOF time-course experiments, staphopain A cleavage of cystatin C and D should be physiologically relevant and occur upon S. aureus infection. Staphopain A hydrolyzed the Glyl 1 bond of cystatin C and the Ala10 bond of cystatin D with similar K-m values of approximately 33 and 32 mu m, respectively. Such N-terminal truncation of cystatin C caused > 300-fold lower inhibition of papain, cathepsin B, L and K, whereas the cathepsin H activity was compromised by a factor of ca. 10. Similarly, truncation of cystatin D caused alleviated inhibition of all endogenous target enzymes investigated. The normal activity of the cystatins is thus down-regulated, indicating that the bacterial enzymes can cause disturbance of the host protease-inhibitor balance. To illustrate the in vivo consequences, a mixed cystatin C assay showed release of cathepsin B activity in the presence of staphopain A. Results presented for the specificity of staphopains when interacting with cystatins as natural protein substrates could aid in the development of therapeutic agents directed toward these proteolytic virulence factors.

Publishing year

2007

Language

English

Pages

437-446

Publication/Series

Biological Chemistry

Volume

388

Issue

4

Document type

Journal article

Publisher

De Gruyter

Topic

  • Basic Medicine
  • Pharmacology and Toxicology
  • Medicinal Chemistry

Keywords

  • protease inhibitors
  • cysteine peptidases
  • Staphylococcus aureus
  • virulence factors

Status

Published

ISBN/ISSN/Other

  • ISSN: 1437-4315