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

Vincents, Bjarne LU ; Önnerfjord, Patrik LU ; Gruca, Milosz ; Potempa, Jan and Abrahamson, Magnus LU (2007) In Biological Chemistry 388(4). p.437-446
Abstract
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,... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
protease inhibitors, cysteine peptidases, Staphylococcus aureus, virulence factors
in
Biological Chemistry
volume
388
issue
4
pages
437 - 446
publisher
De Gruyter
external identifiers
  • wos:000245407000010
  • scopus:34047095311
ISSN
1437-4315
DOI
10.1515/BC.2007.042
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Department of Experimental Medical Science (013210000), Division of Clinical Chemistry and Pharmacology (013250300), Connective Tissue Biology (013230151)
id
56289f04-9a3a-414f-b858-3a0cd5104f60 (old id 166183)
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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17391065&dopt=Abstract
date added to LUP
2016-04-01 12:15:56
date last changed
2020-01-12 09:31:11
@article{56289f04-9a3a-414f-b858-3a0cd5104f60,
  abstract     = {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.},
  author       = {Vincents, Bjarne and Önnerfjord, Patrik and Gruca, Milosz and Potempa, Jan and Abrahamson, Magnus},
  issn         = {1437-4315},
  language     = {eng},
  number       = {4},
  pages        = {437--446},
  publisher    = {De Gruyter},
  series       = {Biological Chemistry},
  title        = {Down-regulation of human extracellular cysteine protease inhibitors by the secreted staphylococcal cysteine proteases, staphopain A and B.},
  url          = {http://dx.doi.org/10.1515/BC.2007.042},
  doi          = {10.1515/BC.2007.042},
  volume       = {388},
  year         = {2007},
}