CK19 stabilizes CFTR at the cell surface by limiting its endocytic pathway degradation

Protein interactions that stabilize the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) at the apical membranes of epithelial cells have not yet been fully elucidated. We identified keratin 19 (CK19 or K19) as a novel CFTR‐interacting protein. CK19 overexpression stabilized both wild...

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Published in:The FASEB journal 2019-11, Vol.33 (11), p.12602-12615
Main Authors: Hou, Xia, Wu, Qingtian, Rajagopalan, Carthic, Zhang, Chunbing, Bouhamdan, Mohamad, Wei, Hongguang, Chen, Xuequn, Zaman, Khalequz, Li, Chunying, Sun, Xiaonan, Chen, Song, Frizzell, Raymond A., Sun, Fei
Format: Article
Language:English
Subjects:
Cystic Fibrosis - genetics
Cystic Fibrosis - metabolism
Cystic Fibrosis - pathology
Cystic Fibrosis Transmembrane Conductance Regulator - genetics
Cystic Fibrosis Transmembrane Conductance Regulator - metabolism
Endocytosis
HEK293 Cells
HeLa Cells
Humans
K19
Keratin-19 - genetics
Keratin-19 - metabolism
lysosomal degradation
Lysosomes - genetics
Lysosomes - metabolism
membrane stability
Multidrug Resistance-Associated Proteins - genetics
Multidrug Resistance-Associated Proteins - metabolism
Mutation
Protein Stability
Proteolysis
Rab7
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Summary:Protein interactions that stabilize the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) at the apical membranes of epithelial cells have not yet been fully elucidated. We identified keratin 19 (CK19 or K19) as a novel CFTR‐interacting protein. CK19 overexpression stabilized both wild‐type (WT)‐CFTR and Lumacaftor (VX‐809)–rescued F508del‐CFTR (where F508del is the deletion of the phenylalanine residue at position 508) at the plasma membrane (PM), promoting Cl– secretion across human bronchial epithelial (HBE) cells. CK19 prevention of Rab7A‐mediated lysosomal degradation was a key mechanism in apical CFTR stabilization. Unexpectedly, CK19 expression was decreased by ~40% in primary HBE cells from homogenous F508del patients with CF relative to non‐CF controls. CK19 also positively regulated multidrug resistance–associated protein 4 expression at the PM, suggesting that this keratin may regulate the apical expression of other ATP‐binding cassette proteins as well as CFTR.—Hou, X., Wu, Q., Rajagopalan, C., Zhang, C., Bouhamdan, M., Wei, H., Chen, X., Zaman, K., Li, C., Sun, X., Chen, S., Frizzell, R. A., Sun, F. CK19 stabilizes CFTR at the cell surface by limiting its endocytic pathway degradation. FASEB J. 33, 12602–12615 (2019). www.fasebj.org
ISSN:0892-6638
1530-6860
1530-6860
DOI:10.1096/fj.201901050R