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c-Cbl facilitates endocytosis and lysosomal degradation of cystic fibrosis transmembrane conductance regulator in human airway epithelial cells

Ye, Siying, Cihil, Kristine, Stolz, Donna Beer, Pilewski, Joseph M., Stanton, Bruce A. and Swiatecka-Urban, Agnieszka 2010, c-Cbl facilitates endocytosis and lysosomal degradation of cystic fibrosis transmembrane conductance regulator in human airway epithelial cells, Journal of biological chemistry, vol. 285, pp. 27008-27018, doi: 10.1074/jbc.M110.139881.

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Title c-Cbl facilitates endocytosis and lysosomal degradation of cystic fibrosis transmembrane conductance regulator in human airway epithelial cells
Author(s) Ye, Siying
Cihil, Kristine
Stolz, Donna Beer
Pilewski, Joseph M.
Stanton, Bruce A.
Swiatecka-Urban, Agnieszka
Journal name Journal of biological chemistry
Volume number 285
Start page 27008
End page 27018
Total pages 11
Publisher American Society for Biochemistry and Molecular Biology
Place of publication Bethesda, Md.
Publication date 2010-08-27
ISSN 0021-9258
1083-351X
Keyword(s) ABC transporter
E3 ubiquitin Ligase
endocytosis
protein Sorting
ubiquitination
lysosomal degradation
Summary Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated Cl− channel expressed in the apical membrane of fluid-transporting epithelia. The apical membrane density of CFTR channels is determined, in part, by endocytosis and the postendocytic sorting of CFTR for lysosomal degradation or recycling to the plasma membrane. Although previous studies suggested that ubiquitination plays a role in the postendocytic sorting of CFTR, the specific ubiquitin ligases are unknown. c-Cbl is a multifunctional molecule with ubiquitin ligase activity and a protein adaptor function. c-Cbl co-immunoprecipitated with CFTR in primary differentiated human bronchial epithelial cells and in cultured human airway cells. Small interfering RNA-mediated silencing of c-Cbl increased CFTR expression in the plasma membrane by inhibiting CFTR endocytosis and increased CFTR-mediated Cl− currents. Silencing c-Cbl did not change the expression of the ubiquitinated fraction of plasma membrane CFTR. Moreover, the c-Cbl mutant with impaired ubiquitin ligase activity (FLAG-70Z-Cbl) did not affect the plasma membrane expression or the endocytosis of CFTR. In contrast, the c-Cbl mutant with the truncated C-terminal region (FLAG-Cbl-480), responsible for protein adaptor function, had a dominant interfering effect on the endocytosis and plasma membrane expression of CFTR. Moreover, CFTR and c-Cbl co-localized and co-immunoprecipitated in early endosomes, and silencing c-Cbl reduced the amount of ubiquitinated CFTR in early endosomes. In summary, our data demonstrate that in human airway epithelial cells, c-Cbl regulates CFTR by two mechanisms: first by acting as an adaptor protein and facilitating CFTR endocytosis by a ubiquitin-independent mechanism, and second by ubiquitinating CFTR in early endosomes and thereby facilitating the lysosomal degradation of CFTR.
Notes Article first published online 4th June, 2010
Language eng
DOI 10.1074/jbc.M110.139881
Field of Research 119999 Medical and Health Sciences not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2010, The American Society for Biochemistry and Molecular Biology, Inc.
Persistent URL http://hdl.handle.net/10536/DRO/DU:30040955

Document type: Journal Article
Collection: School of Medicine
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