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Molecular and Cellular Biology, June 2005, p. 5242-5252, Vol. 25, No. 12
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.12.5242-5252.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Most F508del-CFTR Is Targeted to Degradation at an Early Folding Checkpoint and Independently of Calnexin

Department of Chemistry and Biochemistry, Faculty of Sciences, University of Lisboa, 1749-016 Lisboa, Portugal, and Center for Human Genetics, National Institute of Health, 1649-016 Lisboa, Portugal

Received 9 October 2004/ Returned for modification 16 November 2004/ Accepted 4 March 2005

Biosynthesis and folding of multidomain transmembrane proteins is a complex process. Structural fidelity is monitored by endoplasmic reticulum (ER) quality control involving the molecular chaperone calnexin. Retained misfolded proteins undergo ER-associated degradation (ERAD) through the ubiquitin-proteasome pathway. Our data show that the major degradation pathway of the cystic fibrosis transmembrane conductance regulator (CFTR) with F508del (the most frequent mutation found in patients with the genetic disease cystic fibrosis) from the ER is independent of calnexin. Moreover, our results demonstrate that inhibition of mannose-processing enzymes, unlike most substrate glycoproteins, does not stabilize F508del-CFTR, although wild-type (wt) CFTR is drastically stabilized under the same conditions. Together, our data support a novel model by which wt and F508del-CFTR undergo ERAD from two distinct checkpoints, the mutant being disposed of independently of N-glycosidic residues and calnexin, probably by the Hsc70/Hsp70 machinery, and wt CFTR undergoing glycan-mediated ERAD.

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