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CFTR Inhibitory Factor (CIF) reduces the plasma membrane expression of CFTR by altering intracellular trafficking of CFTR to the lysosomal pathway
Author(s) -
Bomberger Jennifer M.,
MacEachran Daniel,
Ye Siying,
SwiateckaUrban Agnieszka,
O’Toole George,
Stanton Bruce
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1348
Subject(s) - endocytic cycle , cystic fibrosis transmembrane conductance regulator , endosome , cystic fibrosis , microbiology and biotechnology , chemistry , secretion , intracellular , mucociliary clearance , endocytosis , cell , biochemistry , biology , lung , medicine , genetics
The Δ F508‐CFTR mutation, the most common gene mutation in cystic fibrosis (CF), results in diminished plasma membrane expression of CFTR, leading to loss of functional CFTR and altered mucociliary clearance. This impairment promotes chronic infection of CF patients by P. aeruginosa . Previously we reported that a secreted factor from P. aeruginosa (CIF) reduces CFTR‐mediated chloride secretion and the plasma membrane expression of CFTR by decreasing endocytic recycling. The aim of the current study was to investigate the mechanism by which CIF reduces the endocytic recycling of CFTR. CIF applied to the apical side of polarized human airway epithelial cells reduced CFTR in the plasma membrane, followed by a subsequent increase in CFTR labeling in the endosomes, then lysosomes, as determined by Optiprep subcellular compartment fractionation experiments. Co‐immunoprecipitation studies revealed that CIF decreased the association of CFTR with Rab11a, concurrent with an increase in association of CFTR with Rab4a and Rab7. Lysosomal inhibitors blocked the degradation of CFTR by CIF, whereas proteosomal inhibitors had no effect. These studies demonstrate that CIF induces a redistribution of CFTR trafficking from the endocytic recycling pathway to the degradative pathway. In addition, this data suggests that chronic infection of P. aeruginosa in the CF lung may impact the efficacy of therapeutics developed to increase plasma membrane expression of the ΔF508‐CFTR.