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A more recent version of this article appeared on June 1, 2004 Originally published as MBC in Press, 10.1091/mbc.E04-03-0176 on April 13, 2004
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Submitted on March 3, 2004
Accepted on March 29, 2004
F508 CFTR
1 Mayo Clinic College of Medicine, S. C. Johnson Medical Research Center, Department of Biochemistry and Molecular Biology, Mayo Clinic, Scottsdale, AZ 85259 USA
2 Mayo Clinic College of Medicine, Department of Biochemistry and Molecular Biology and Thoracic Diseases Research Unit, Mayo Clinic, Rochester, MN 55905 USA
3 Mayo Clinic College of Medicine, S. C. Johnson Medical Research Center, 13400 E. Shea Blvd, Scottsdale, AZ 85259 USA
* Corresponding author. E-mail address: riordan{at}mayo.edu.
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 ER, but if induced to do so at reduced temperature is short-lived at the surface. We utilized 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 TGN. 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.
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