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Pseudomonas aeruginosa elastase disables proteinase-activated receptor 2 in respiratory epithelial cells

Dulon, S., Leduc, D., Cottrell, G. S., D'Alayer, J., Hansen, K. K., Bunnett, N. W., Hollenberg, M. D., Pidard, D. and Chignard, M. (2005) Pseudomonas aeruginosa elastase disables proteinase-activated receptor 2 in respiratory epithelial cells. American Journal of Respiratory Cell and Molecular Biology, 32 (5). pp. 411-419. ISSN 1044-1549

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To link to this item DOI: 10.1165/rcmb.2004-0274OC

Abstract/Summary

Pseudomonas aeruginosa, a major lung pathogen in cystic fibrosis (CF) patients, secretes an elastolytic metalloproteinase (EPa) contributing to bacterial pathogenicity. Proteinase-activated receptor 2 (PAR2), implicated in the pulmonary innate defense, is activated by the cleavage of its extracellular N-terminal domain, unmasking a new N-terminal sequence starting with SLIGKV, which binds intramolecularly and activates PAR2. We show that EPa cleaves the N-terminal domain of PAR2 from the cell surface without triggering receptor endocytosis as trypsin does. As evaluated by measurements of cytosolic calcium as well as prostaglandin E(2) and interleukin-8 production, this cleavage does not activate PAR2, but rather disarms the receptor for subsequent activation by trypsin, but not by the synthetic receptor-activating peptide, SLIGKV-NH(2). Proteolysis by EPa of synthetic peptides representing the N-terminal cleavage/activation sequences of either human or rat PAR2 indicates that cleavages resulting from EPa activity would not produce receptor-activating tethered ligands, but would disarm PAR2 in regard to any further activating proteolysis by activating proteinases. Our data indicate that a pathogen-derived proteinase like EPa can potentially silence the function of PAR2 in the respiratory tract, thereby altering the host innate defense mechanisms and respiratory functions, and thus contributing to pathogenesis in the setting of a disease like CF.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
No Reading authors. Back catalogue items
ID Code:30279
Uncontrolled Keywords:Animals Bacterial Proteins/*metabolism Cell Line Humans Pancreatic Elastase/*metabolism Peptide Fragments/genetics/metabolism Pseudomonas aeruginosa/*enzymology Receptor, PAR-2/genetics/*metabolism Respiratory Mucosa/*cytology/*metabolism
Publisher:American Thoracic Society

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