The Distribution and Role of the CFTR Protein in the Intracellular Compartments

Abstract

Cystic fibrosis is a hereditary disease that mainly affects secretory organs in humans. It is caused by mutations in the gene encoding CFTR with the most common phenylalanine deletion at position 508. CFTR is an anion channel mainly conducting Cl^- across the apical membranes of many different epithelial cells, the impairment of which causes dysregulation of epithelial fluid secretion and thickening of the mucus. This, in turn, leads to the dysfunction of organs such as the lungs, pancreas, kidney and liver. The CFTR protein is mainly localized in the plasma membrane; however, there is a growing body of evidence that it is also present in the intracellular organelles such as the endosomes, lysosomes, phagosomes and mitochondria. Dysfunction of the CFTR protein affects not only the ion transport across the epithelial tissues, but also has an impact on the proper functioning of the intracellular compartments. The review aims to provide a summary of the present state of knowledge regarding CFTR localization and function in intracellular compartments, the physiological role of this localization and the consequences of protein dysfunction at cellular, epithelial and organ levels. An in-depth understanding of intracellular processes involved in CFTR impairment may reveal novel opportunities in pharmacological agents of cystic fibrosis.

Keywords: chloride channels; cystic fibrosis transmembrane conductance regulator; intracellular organelle; ion transport.

Figure 1

Summary of CFTR role in the intracellular organelles. (A–D) show the effect of CFTR impairment on intracellular vesicles. In phagosomes (A) of CFTR-depleted cells HOCl formation from Cl⁻, O₂ and H₂O₂ by myeloperoxidase (MPO) is impaired. In healthy cells the process results in a phagosomal pH increase which is compensated by low pH of lysosomes fusing with phagosomes to form phagolysosomes. Changes in pH of other intracellular vesicles (lysosomes, Golgi) varies. There are three different pathways indicated. (B) CFTR malfunction may lead to defective acidification due to a deficiency in the counter anion transport of Cl⁻, required for proper H⁺−ATPase function and low pH maintenance. (C) Another mechanism of CFTR malfunction involves the lack of CFTR inhibitory effect on endothelial sodium channel (ENaC), which promotes outward sodium cation transport and results in hyperacidification. (D) No effect of CFTR on vesicle pH indicates other channels involved in proper acidification such as ClC-5. (E) In cystic fibrosis there is increased concentration of misfolded CFTR protein in the endoplasmic reticulum, which causes increased SERCA activity and the release of Ca²⁺ from ER to cytoplasm. (F) The presence of CFTR in mitochondria is poorly documented. The effect of plasma membrane CFTR depletion on mitochondria is associated with: complex I (CI) of electron transport chain inhibition, lower ATP production, a decrease in mitochondrial membrane potential (Δψ), MCU inhibition and cytochrome c release. The consequence of MCU inhibition is Ca²⁺ release and NFκB activation, which leads to inflammation. Besides Ca²⁺, ROS generated by mitochondria of CFTR-depleted cells also mediate inflammation as well as mitochondrial DNA and lipid peroxidation. Created with BioRender.com.