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Published online 8 March 2004. doi:10.1083/jcb.200312018
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 164, Number 6, 923-933
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Article

 Misfolding diverts CFTR from recycling to degradation : quality control at early endosomes



Manu Sharma1,2, Francesca Pampinella1,2, Csilla Nemes1,2, Mohamed Benharouga1,2, Jeffrey So1, Kai Du1, Kristi G. Bache4, Blake Papsin1, Noa Zerangue3, Harald Stenmark4, and Gergely L. Lukacs1,2

1 Hospital for Sick Children Research Institute, Toronto, Ontario M5G 1X8, Canada
2 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1L5, Canada
3 Howard Hughes Medical Institute, Department of Physiology and Biochemistry, University of California, San Francisco, San Francisco, CA 94143
4 Department of Biochemistry, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway

Address correspondence to Gergely L. Lukacs, Hospital for Sick Children, Program in Cell and Lung Biology, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Tel.: (416) 813-5125. Fax: (416) 813-5771. email: glukacs{at}sickkids.ca

To investigate the degradation mechanism of misfolded membrane proteins from the cell surface, we used mutant cystic fibrosis transmembrane conductance regulators (CFTRs) exhibiting conformational defects in post-Golgi compartments. Here, we show that the folding state of CFTR determines the post-endocytic trafficking of the channel. Although native CFTR recycled from early endosomes back to the cell surface, misfolding prevented recycling and facilitated lysosomal targeting by promoting the ubiquitination of the channel. Rescuing the folding defect or down-regulating the E1 ubiquitin (Ub)-activating enzyme stabilized the mutant CFTR without interfering with its internalization. These observations with the preferential association of mutant CFTRs with Hrs, STAM-2, TSG101, hVps25, and hVps32, components of the Ub-dependent endosomal sorting machinery, establish a functional link between Ub modification and lysosomal degradation of misfolded CFTR from the cell surface. Our data provide evidence for a novel cellular mechanism of CF pathogenesis and suggest a paradigm for the quality control of plasma membrane proteins involving the coordinated function of ubiquitination and the Ub-dependent endosomal sorting machinery.

Key Words: recycling; sorting; mutation; endocytosis; ubiquitin receptors

The online version of this article includes supplemental material.

Abbreviations used in this paper: CFTR, cystic fibrosis transmembrane conductance regulator; CHX, cycloheximide; ESCRT, endosomal sorting complex required for transport; Hrs, hepatocyte growth factor–regulated tyrosine kinase substrate; MVB, multivesicular body; STAM, signal-transducing adaptor molecule; Ub, ubiquitin; Vps, vacuolar protein sorting; wt, wild type.


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