Abstract
The multi-organ disease cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein, a cAMP regulated chloride (Cl−) and bicarbonate (HCO3−) ion channel expressed at the apical plasma membrane (PM) of epithelial cells. Reduced CFTR protein results in decreased Cl− secretion and excessive sodium reabsorption in epithelial cells, which consequently leads to epithelial dehydration and the accumulation of thick mucus within the affected organs, such as the lungs, pancreas, gastrointestinal (GI) tract, reproductive system and sweat glands. However, CFTR has been implicated in other functions besides transporting ions across epithelia. The rising number of references concerning its association to actin cytoskeleton organization, epithelial cell junctions and extracellular matrix (ECM) proteins suggests a role in the formation and maintenance of epithelial apical basolateral polarity. This review will focus on recent literature (the last 10 years) substantiating the role of CFTR in cell junction formation and actin cytoskeleton organization with its connection to the ECM.
Highlights
A proper physical barrier function is key to a structured epithelium and this property is mediated by different cell–cell junctions that extracellularly link the epithelial cells together while providing intracellular connections with different elements of the cytoskeleton in a functional continuum [1]
We recently investigated epithelial–mesenchymal transition (EMT), which had been suggested to occur in Cystic Fibrosis (CF); it is a process which involves the disruption of cell junctions, cell adhesion, cell polarity, remodelling of the cytoskeleton, and changes in cell–matrix adhesion
An emerging body of literature shows that CF transmembrane conductance regulator (CFTR) is tightly associated with actin cytoskeleton organization and with cell junction formation in epithelial cells
Summary
A proper physical barrier function is key to a structured epithelium and this property is mediated by different cell–cell junctions that extracellularly link the epithelial cells together while providing intracellular connections with different elements of the cytoskeleton in a functional continuum [1]. TJs and AJs are important due to their direct connection to the cytoskeleton through actin and microfilaments, as well as to polarity protein complexes, establishing and maintaining an apical basolateral polarity critical for proper epithelial cell function [1,4,5]. Many studies have reported, as ‘secondary’ effects of CFTR dysfunction, that CF epithelia display a disorganized actin cytoskeleton [10–12] and high paracellular permeability in parallel with low transepithelial electrical resistance (TEER). All these features are consistent with disrupted tight junction (TJ) structure [13–16], suggesting that CFTR has important roles in the maintenance of the proper structure and function of the epithelia. We aim to establish that CF is not ‘merely’ a channelopathy/ion channel disease, and a disorder of epithelial differentiation, evident at the level of the structure and function of the cytoskeleton and cell junctions, as previously proposed [17]
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