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A Pseudomonas aeruginosa toxin that hijacks the host ubiquitin proteolytic system

Jennifer M Bomberger1, Siying Ye, Daniel P Maceachran

  • 1Microbiology and Immunology, Dartmouth Medical School, Hanover, New Hampshire, United States of America. jbomberger@dartmouth.edu

Plos Pathogens
|April 2, 2011
PubMed

Insights

Pseudomonas aeruginosa toxin Cif disrupts lung pathogen clearance by targeting CFTR protein degradation. This bacterial toxin inhibits mucociliary clearance, contributing to chronic lung infections in patients with COPD, pneumonia, cystic fibrosis, and bronchiectasis.

Area of Science:

  • Microbiology
  • Cell Biology
  • Pathogen-Host Interactions

Background:

  • Pseudomonas aeruginosa is an opportunistic pathogen causing chronic lung infections in patients with COPD, pneumonia, cystic fibrosis (CF), and bronchiectasis.
  • Cystic fibrosis transmembrane conductance regulator (CFTR)-mediated chloride secretion is crucial for mucociliary clearance in the airways.
  • Reduced mucociliary clearance impairs the ability to clear pathogens, leading to chronic lung infections.

Purpose of the Study:

  • To investigate the mechanism by which the Pseudomonas aeruginosa toxin Cif reduces CFTR-mediated chloride secretion.
  • To elucidate how Cif affects the trafficking and degradation of the CFTR protein in human airway epithelial cells.

Main Methods:

  • Investigated the effect of Cif on CFTR localization and degradation in human airway epithelial cells.
  • Utilized cell biology techniques to analyze protein trafficking pathways, including endocytosis, recycling, and lysosomal degradation.
  • Examined the interaction between Cif, G3BP1, and USP10 in regulating CFTR deubiquitination and stability.

Main Results:

  • Cif redirects endocytosed CFTR from recycling endosomes to lysosomes.
  • Cif stabilizes an inhibitory effect of G3BP1 on the deubiquitinating enzyme (DUB) USP10.
  • This leads to reduced USP10-mediated deubiquitination of CFTR and increased lysosomal degradation of CFTR.
  • This is the first reported instance of a bacterial toxin modulating a host DUB's activity.

Conclusions:

  • Pseudomonas aeruginosa Cif toxin inhibits CFTR-mediated chloride secretion by promoting CFTR degradation.
  • Cif's mechanism involves hijacking host cell machinery to target CFTR for lysosomal degradation via USP10 inhibition.
  • This bacterial toxin contributes to impaired mucociliary clearance and chronic lung infections by P. aeruginosa.

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