Serum and Glucocorticoid-Inducible Kinase1 Increases Plasma Membrane wt-CFTR in Human Airway Epithelial Cells by Inhibiting Its Endocytic Retrieval

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From: PLoS ONE(Vol. 9, Issue 2)
Publisher: Public Library of Science
Document Type: Article
Length: 7,626 words
Lexile Measure: 1550L

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Author(s): Jennifer M. Bomberger 1, Bonita A. Coutermarsh 2, Roxanna L. Barnaby 2, J. Denry Sato 3, M. Christine Chapline 3, Bruce A. Stanton 2,3,*


The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a cyclic-AMP regulated chloride (Cl) channel residing in the apical plasma membrane of a variety of epithelial cells, including those in the lungs [1]. Cl secretion via wt-CFTR is critical in maintaining the airway surface liquid volume, and therefore, is essential for effective mucociliary clearance, which mechanically clears debris and pathogens from the airways and serves a vital role in innate immunity [2]. Individuals with defective CFTR function, for example patients with Cystic Fibrosis or chronic smokers, have chronic lung infections due to a lack of clearance of respiratory pathogens [2], [3]. wt-CFTR function and localization in the cell are highly regulated by a complex of proteins that modulates its biosynthesis, trafficking to and from the plasma membrane, and channel activity [1], [4]-[7]. Once delivered to the apical plasma membrane of airway epithelial cells, wt-CFTR is rapidly endocytosed from the plasma membrane and then undergoes rapid and efficient recycling back to the plasma membrane [1], [8]-[11]. We and others have demonstrated that the endocytic trafficking of wt-CFTR is regulated by numerous protein-protein interactions, as well as by ubiquitination [1], [4]-[7], [12].

SGK1 is transcriptionally regulated by a variety of stimuli including stress, serum, and a large number of cytokines and hormones including gluococorticoids [13]. SGK1 regulates a number of ion channels including ENaC, CFTR, and ROMK that play important roles in sodium and potassium excretion by the kidneys, as well as in the maintenance of airway surface liquid volume in the lungs [5], [13]. A variant of SGK1 is associated with increased blood pressure, obesity and type II diabetes [13]. Previously, others and we have shown that SGK1 stimulates wt-CFTR mediated chloride (Cl) currents in Xenopus oocytes by increasing the amount of wt-CFTR protein in the plasma membrane [14], [15]. Moreover, SGK1 also increases the plasma membrane abundance of wt-CFTR in the plasma membrane of mitochondrion rich cells in the gill of Fundulus heteroclitus [16], [17]. In a recent study Caohuy et al [18] demonstrated that dexamethasone increases the plasma membrane expression of both wt-CFTR and [DELTA]F508-CFTR in pancreatic cells, and that RNA interference of SGK1 blocks the stimulatory effect of dexamethasone on plasma membrane [DELTA]F508-CFTR, a finding suggesting that SGK1 increases plasma membrane CFTR. In addition, two recent studies [19], [20] have shown that dexamethasone increases wt-CFTR abundance in airway cell lines. However, the mechanism whereby SGK1 increased the plasma membrane abundance of wt-CFTR has not been examined. Thus, the primary goal of this study was to elucidate the cellular mechanism whereby SGK1 increases plasma membrane wt-CFTR. The data herein is novel because it demonstrates that SGK1 selectively increases wt-CFTR in the plasma membrane of human airway epithelial cells by inhibiting its endocytic retrieval from the membrane.

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The role of SGK1 in regulating plasma membrane wt-CFTR was studied in human airway epithelial...

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