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.
Highlights
Continuous mass and energy transfer between the cells and their environment is necessary for a sustained life
The first step of CFTR folding is represented by the positioning of the MSD1 domain into the endoplasmic reticulum (ER) membrane [70] followed by the synthesis of the NBD1 domain
It was proven that chloride channels, such as CFTR, are present in endosomes in Chinese hamster ovary (CHO) cells; the authors question the role of the counter ion conductance as the primary factor limiting acidification of the vesicles [91]
Summary
Continuous mass and energy transfer between the cells and their environment is necessary for a sustained life. Intracellular ion channels play a vital role in cellular and organ physiology by maintaining and regulating the ionic homeostasis of intracellular organelles They were discovered and widely described in the endoplasmic reticulum (ryanodine receptors, RyRs; inositol triphosphate receptor, IP3R) [2], lysosomes (Na+ and K+ selective channels; lysosomal Ca2+ channels; mucopilin subfamily of transient receptor potential channels, TRPMLs) [3] and nucleus (nuclear pore complexes, NPCs; Ca2+-ATP-ase) [4]. The soluble CLIC forms were shown to have enzymatic activity, which might be important in terms of protecting the cells against oxidation [13] How these proteins form functional ion channels is not completely understood, but they are known to be present in the intracellular membranes [9,14,15,16,17]. An updated characterization of CFTR is presented, with the focus on intracellular localization and function
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