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J. Biol. Chem., Vol. 283, Issue 2, 833-839, January 11, 2008

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Cystic Fibrosis Transmembrane Conductance Regulator Trafficking Is Mediated by the COPI Coat in Epithelial Cells^*

Jessica Rennolds, Cristy Tower, Lois Musgrove^¶, Lijuan Fan^||, Kevin Maloney, John Paul Clancy^||, Kevin L. Kirk^¶, Elizabeth Sztul, and Estelle Cormet-Boyaka¹

From the Division of Pulmonary, Critical Care, and Sleep Medicine, The Ohio State University, Columbus, Ohio 43210 and Departments of Cell Biology, ^¶Physiology and Biophysics, and ^||Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama 35294

Cystic fibrosis (CF) is caused by defects in the CF transmembrane conductance regulator (CFTR) that functions as a chloride channel in epithelial cells. The most common cause of CF is the abnormal trafficking of CFTR mutants. Therefore, understanding the cellular machineries that transit CFTR from the endoplasmic reticulum to the plasma membrane (PM) is important. The coat protein complex I (COPI) has been implicated in the anterograde and retrograde transport of proteins and lipids between the endoplasmic reticulum and the Golgi. Here, we investigated the role of COPI in CFTR trafficking. Blocking COPI recruitment to membranes by expressing an inactive form of the GBF1 guanine nucleotide exchange factor for ADP-ribosylation factor inhibits CFTR trafficking to the PM. Similarly, inhibiting COPI dissociation from membranes by expressing a constitutively active ADP-ribosylation factor 1 mutant arrests CFTR within disrupted Golgi elements. To definitively explore the relationship between COPI and CFTR in epithelial cells, we depleted β-COP from the human colonic epithelial cell HT-29Cl.19A using small interfering RNA. β-COP depletion did not affect CFTR synthesis but impaired its trafficking to the PM. The arrest occurred pre-Golgi as shown by reduced level of glycosylation. Importantly, decreased trafficking of CFTR had a functional consequence as cells depleted of β-COP showed decreased cAMP-activated chloride currents. To explore the mechanism of COPI action in CFTR traffic we tested whether CFTR was COPI cargo. We discovered that the -, β-, and -subunits of COPI co-immunoprecipitated with CFTR. Our results indicate that the COPI complex plays a critical role in CFTR trafficking to the PM.

Received for publication, August 6, 2007 , and in revised form, October 4, 2007.

^* This work was supported by a grant from the Davis Heart and Lung Research Institute at The Ohio State University (Intramural Thematic Grant Program). 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: 201 Davis Heart and Lung Research Inst., 473 W. 12th Ave., Columbus, OH 43201. Tel.: 614-293-0580; Fax: 614-293-4799; E-mail: estelle.boyaka{at}osumc.edu.

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