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Infection and Immunity, August 2007, p. 3902-3912, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.00338-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Pseudomonas aeruginosa Secreted Protein PA2934 Decreases Apical Membrane Expression of the Cystic Fibrosis Transmembrane Conductance Regulator{triangledown}

Daniel P. MacEachran,1 Siying Ye,2 Jennifer M. Bomberger,2 Deborah A. Hogan,1 Agnieszka Swiatecka-Urban,2 Bruce A. Stanton,2 and George A. O'Toole1*

Department of Microbiology and Immunology,1 Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire2

Received 3 March 2007/ Returned for modification 9 April 2007/ Accepted 30 April 2007

We previously reported that Pseudomonas aeruginosa PA14 secretes a protein that can reduce the apical membrane expression of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Here we report that we have used a proteomic approach to identify this secreted protein as PA2394, and we have named the gene cif, for CFTR inhibitory factor. We demonstrate that Cif is a secreted protein and is found associated with outer membrane-derived vesicles. Expression of Cif in Escherichia coli and purification of the C-terminal six-His-tagged Cif protein showed that Cif is necessary and sufficient to mediate the reduction in apical membrane expression of CFTR and a concomitant reduction in CFTR-mediated Cl– ion secretion. Cif demonstrates epoxide hydrolase activity in vitro and requires a highly conserved histidine residue identified in {alpha}/ß hydrolase family enzymes to catalyze this reaction. Mutating this histidine residue also abolishes the ability of Cif to reduce apical membrane CFTR expression. Finally, we demonstrate that the cif gene is expressed in the cystic fibrosis (CF) lung and that nonmucoid isolates of P. aeruginosa show greater expression of the gene than do mucoid isolates. We propose a model in which the Cif-mediated decrease in apical membrane expression of CFTR by environmental isolates of P. aeruginosa facilitates the colonization of the CF lung by this microbe.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Dartmouth Medical School, Hanover, NH 03755. Phone: (603) 650-1248. Fax: (603) 650-1245. E-mail: georgeo{at}Dartmouth.edu

{triangledown} Published ahead of print on 14 May 2007.

Editor: D. L. Burns

Infection and Immunity, August 2007, p. 3902-3912, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.00338-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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