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Cited by 139Blood Coagulation and Thrombosis MechanismsProtease and Inhibitor MechanismsBacterial biofilms and quorum sensing

Pseudomonas aeruginosa Elastase Disables Proteinase-Activated Receptor 2 in Respiratory Epithelial Cells

Dulon, Sophie, Leduc, Dominique, Cottrell, Graeme S., D'Alayer, Jacques, Hansen, Kristina K., Bunnett, Nigel W., Hollenberg, Morley D., Pidard, Dominique +1 more·2005·American Journal of Respiratory Cell and Molecular Biology
DOI 10.1165/rcmb.2004-0274oc
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Abstract

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 E2 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-NH2. 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.

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Crossref · 10.1165/rcmb.2004-0274oc

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  • LasB from Pseudomonas aeruginosa and GelE from Enterococcus faecalis degrade the N-terminal of PAR-2, contributing to food sensitivities and intestinal inflammation in preclinical mouse models.

    “Of relevance, LasB from Pseudomonas aeruginosa,18,143 and GelE from Enterococcus faecalis144 degrade the N-terminal of PAR-2, contributing to food sensitivities and intestinal inflammation in preclinical mouse models.”

    From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [143]

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Authors
Dulon, S., Leduc, D., Cottrell, G. S., D'Alayer, J., Hansen, K. K., Bunnett, N. W., Hollenberg, M. D., Pidard, D., & Chignard, M.
Affiliations
  • Inserm (FR)
  • Unité de Défense Innée et Inflammation/Inserm Equipe 336, and Plate-Forme d'Analyse et de Microséquençage des Protéines, Institut Pasteur, Paris, France; Departments of Surgery and Physiology, University of California, San Francisco, California; and Department of Pharmacology and Therapeutics and Department of Medicine, University of Calgary, Calgary, Alberta, Canada
ORCID
Venue
American Journal of Respiratory Cell and Molecular Biology
Publisher
Oxford University Press (OUP)
Published
2005-05-01
Volume
32
Issue
5
Pages
411-419
ISSN
  • 1044-1549 (ISSN-L)
  • 1535-4989
DOI
10.1165/rcmb.2004-0274oc
OpenAlex
W2077544911
Cited by
139
References
48
Citations by year
2026: 3 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 6 · 2021: 3 · 2020: 7 · 2019: 6 · 2018: 3 · 2017: 8 · 2016: 3 · 2015: 3 · 2014: 14 · 2013: 8 · 2012: 8
FWCI
6.10
Type
journal article
Language
en
Open access
closed
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • American Journal of Respiratory Cell and Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (DK 43207, DK-57480)
Topics
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bacterial biofilms and quorum sensing
Keywords
Pseudomonas aeruginosa, elastase, protease-activated receptor 2, PAR2, cystic fibrosis, receptor proteolysis, trypsin activation, airway epithelial cells, innate immunity, prostaglandin E2, interleukin-8, intracellular calcium, bacterial pathogenesis
MeSH terms
Animals, Bacterial Proteins, Cell Line, Humans, Pancreatic Elastase, Peptide Fragments, Pseudomonas aeruginosa, Respiratory Mucosa, Receptor, PAR-2

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