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EXTRACELLULAR MATRIX, CELL INTERACTIONS

Cystic fibrosis transmembrane conductance regulator and caveolin-1 regulate epithelial cell internalization of Pseudomonas aeruginosa

¹Department of Biological Chemistry and Molecular Pharmacology and ²Department of Medicine, Harvard Medical School; ³Channing Laboratory, Department of Medicine and ⁴Hematology Division, Brigham and Women's Hospital; and ⁵Molecular and Vascular Medicine Unit and Renal Division, Beth Israel Deaconess Medical Center; Boston, Massasschusettes

Submitted 15 October 2008 ; accepted in final form 16 April 2009

Patients with cystic fibrosis (CF) exhibit defective innate immunity and are susceptible to chronic lung infection with Pseudomonas aeruginosa. To investigate the molecular bases for the hypersusceptibility of CF patients to P. aeruginosa, we used the IB3-1 cell line with two defective CF transmembrane conductance regulator (CFTR) genes (F508/W1282X) to generate isogenic stable, clonal lung epithelial cells expressing wild-type (WT)-CFTR with an NH₂-terminal green fluorescent protein (GFP) tag. GFP-CFTR exhibited posttranslational modification, subcellular localization, and anion transport function typical of WT-CFTR. P. aeruginosa internalization, a component of effective innate immunity, required functional CFTR and caveolin-1, as shown by: 1) direct correlation between GFP-CFTR expression levels and P. aeruginosa internalization; 2) enhanced P. aeruginosa internalization by aminoglycoside-induced read through of the CFTR W1282X allele in IB3-1 cells; 3) decreased P. aeruginosa internalization following siRNA knockdown of GFP-CFTR or caveolin-1; and 4) spatial association of P. aeruginosa with GFP-CFTR and caveolin-1 at the cell surface. P. aeruginosa internalization also required free lateral diffusion of GFP-CFTR, allowing for bacterial coclustering with GFP-CFTR and caveolin-1 at the plasma membrane. Thus efficient initiation of innate immunity to P. aeruginosa requires formation of an epithelial "internalization platform" involving both caveolin-1 and functional, laterally mobile CFTR.

chronic lung infection; green fluorescent protein; innate immunity; lateral diffusion

This article has been cited by other articles:

				P. L. Zeitlin Pseudomonas aeruginosa: can studies in engineered cells tell us why is it such a problem in people with cystic fibrosis? Focus on "Cystic fibrosis transmembrane conductance regulator and caveolin-1 regulate epithelial cell internalization of Pseudomonas aeruginosa" Am J Physiol Cell Physiol, August 1, 2009; 297(2): C235 - C237. [Full Text] [PDF]