Abstract
Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen chronically infecting the lungs of patients with chronic obstructive pulmonary disease (COPD), pneumonia, cystic fibrosis (CF), and bronchiectasis. Cif (PA2934), a bacterial toxin secreted in outer membrane vesicles (OMV) by P. aeruginosa, reduces CFTR-mediated chloride secretion by human airway epithelial cells, a key driving force for mucociliary clearance. The aim of this study was to investigate the mechanism whereby Cif reduces CFTR-mediated chloride secretion. Cif redirected endocytosed CFTR from recycling endosomes to lysosomes by stabilizing an inhibitory effect of G3BP1 on the deubiquitinating enzyme (DUB), USP10, thereby reducing USP10-mediated deubiquitination of CFTR and increasing the degradation of CFTR in lysosomes. This is the first example of a bacterial toxin that regulates the activity of a host DUB. These data suggest that the ability of P. aeruginosa to chronically infect the lungs of patients with COPD, pneumonia, CF, and bronchiectasis is due in part to the secretion of OMV containing Cif, which inhibits CFTR-mediated chloride secretion and thereby reduces the mucociliary clearance of pathogens.
Highlights
Respiratory infections are the greatest cause of disease worldwide [1]
We propose that the ability of P. aeruginosa to chronically infect the lungs of patients with cystic fibrosis (CF), pneumonia, chronic obstructive pulmonary disease (COPD), and bronchiectasis is due in part to the secretion of outer membrane vesicles (OMV) containing Cif, which inhibits CFTR mediated chloride secretion and reduces the mucociliary clearance of pathogens
After P. aeruginosa OMV treatment, CFTR was measured in cell lysates by Western blot analysis and in the apical plasma membrane by cell surface biotinylation followed by Western blot analysis
Summary
Respiratory infections are the greatest cause of disease worldwide [1]. A study by the World Health Organization (WHO) determined that the global disease burden of lung infections exceeds that of HIV/AIDS, cancer and heart disease and has since 1990 [1]. We have previously demonstrated that outer membrane vesicles (OMV) secreted by P. aeruginosa deliver multiple virulence factors into host human airway epithelial cells via a mechanism involving OMV fusion with airway cell plasma membrane lipid rafts and trafficking via an N-WASP induced actin pathway to deliver OMV cargo directly to the host cytoplasm [2]. This provides a mechanism for P. aeruginosa to alter host cell biology without the need for contact with airway epithelial cells, an important consideration in respiratory diseases where P. aeruginosa resides primarily in the mucus layer above the host airway epithelium [2]. The mechanism by which Cif reduces the recycling of endocytic vesicles containing CFTR is currently unknown, and characterizing this mechanism was the goal of the present study
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
