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J. Biol. Chem., Vol. 280, Issue 44, 36762-36772, November 4, 2005

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The Short Apical Membrane Half-life of Rescued F508-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Results from Accelerated Endocytosis of F508-CFTR in Polarized Human Airway Epithelial Cells^*

Agnieszka Swiatecka-Urban1, Andrea Brown, Sophie Moreau-Marquis, Janhavi Renuka, Bonita Coutermarsh, Roxanna Barnaby, Katherine H. Karlson, Terence R. Flotte, Mitsunori Fukuda¶, George M. Langford||, and Bruce A. Stanton

From the Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire 03755, Department of Pediatrics, University of Florida College of Medicine, Gainesville, Florida 32610, ^¶Fukuda Initiative Research Unit, Institute of Physical and Chemical Research (RIKEN), 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan, and ^||Department of Biological Sciences, Dartmouth College, Hanover, New Hampshire 03755

The most common mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in individuals with cystic fibrosis, F508, causes retention of F508-CFTR in the endoplasmic reticulum and leads to the absence of CFTR Cl^- channels in the apical plasma membrane. Rescue of F508-CFTR by reduced temperature or chemical means reveals that the F508 mutation reduces the half-life of F508-CFTR in the apical plasma membrane. Because F508-CFTR retains some Cl^- channel activity, increased expression of F508-CFTR in the apical membrane could serve as a potential therapeutic approach for cystic fibrosis. However, little is known about the mechanisms responsible for the short apical membrane half-life of F508-CFTR in polarized human airway epithelial cells. Accordingly, the goal of this study was to determine the cellular defects in the trafficking of rescued F508-CFTR that lead to the decreased apical membrane half-life of F508-CFTR in polarized human airway epithelial cells. We report that in polarized human airway epithelial cells (CFBE41o-) the F508 mutation increased endocytosis of CFTR from the apical membrane without causing a global endocytic defect or affecting the endocytic recycling of CFTR in the Rab11a-specific apical recycling compartment.

Received for publication, August 12, 2005 , and in revised form, August 29, 2005.

^* This study was supported by National Institutes of Health Grants P20-RR018787 (to A. S.-U. and B. A. S.) and RO1-DK45881 and RO1-DK34533 (to B. A. S.) from the National Center for Research Resources, a Shwachman Award SWIATE03QO from the Cystic Fibrosis Foundation (to A. S.-U.), and a Research Development Program grant from the Cystic Fibrosis Foundation (to B. A. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 603-650-1534; Fax: 603-650-1130; E-mail: Agnieszka.Swiatecka-Urban{at}Dartmouth.edu.

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