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Vol. 15, Issue 6, 2684-2696, June 2004
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F508 Cystic Fibrosis Transmembrane Conductance Regulator
* Mayo Clinic College of Medicine, S.C. Johnson Medical Research Center, Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, Arizona 85259;
Mayo Clinic College of Medicine, Department of Biochemistry and Molecular Biology and Thoracic Diseases Research Unit, Mayo Clinic, Rochester, Minnesota 55905
Submitted March 3, 2004;
Revised March 29, 2004;
Accepted March 29, 2004
Monitoring Editor: Vivek Malhotra
Intracellular trafficking of cystic fibrosis transmembrane conductance regulator (CFTR) is a focus of attention because it is defective in most patients with cystic fibrosis. 
F508 CFTR, which does not mature conformationally, normally does not exit the endoplasmic reticulum, but if induced to do so at reduced temperature is short-lived at the surface. We used external epitope-tagged constructs to elucidate the itinerary and kinetics of wild type and F508 CFTR in the endocytic pathway and visualized movement of CFTR from the surface to intracellular compartments. Modulation of different endocytic steps with low temperature (16°C) block, protease inhibitors, and overexpression of wild type and mutant Rab GTPases revealed that surface CFTR enters several different routes, including a Rab5-dependent initial step to early endosomes, then either Rab11-dependent recycling back to the surface or Rab7-regulated movement to late endosomes or alternatively Rab9-mediated transit to the trans-Golgi network. Without any of these modulations F508 CFTR rapidly disappears from and does not return to the cell surface, confirming that its altered structure is detected in the distal as well as proximal secretory pathway. Importantly, however, the mutant protein can be rescued at the plasma membrane by Rab11 overexpression, proteasome inhibitors, or inhibition of Rab5-dependent endocytosis.
Abbreviations used: CFTR, cystic fibrosis transmembrane conductance regulator; DN, dominant-negative; DsRed, red fluorescent protein; EGFP, enhanced green fluorescent protein; EEA1, early endosomal antigen 1; Extope-CFTR, external-epitope tagged CFTR; EL, extracytoplasmic loop; PDZ, PSD-95/discs large/ZO-1; TGN trans-Golgi network; UIM, ubiquitin-interacting motif.
Online version of this article contains supporting material. Online version is available at www.molbiolcell.org.
Corresponding author. E-mail address: riordan{at}mayo.edu.
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