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.

Recommended Tool Compounds for Modifying the Cystic Fibrosis Transmembrane Conductance Regulator Channel Variants

“…24,25 CFTR channels still exhibit the characteristic structure of the ATP-binding cassette protein superfamily. 26 It is composed of five functional domains overall, two membrane spanning domains (MSDs) that form an ion transport pathway, two cytosolic nucleotide-binding domains (NBDs) which ATP binds to, and a cytosolic regulatory domain (Rdomain) located between two MSDs, and needs to be phosphorylated by Protein Kinase A for CFTR to function effectively (Figure 1). 24,27 One of the primary functions of CFTR is working as an anion channel; it is selectively permeable to various halide ions with the highest conductance to chloride, as well as allows various polyatomic anions to permeate such as nitrate and bicarbonate.…”

“…One of the primary functions of CFTR is working as an anion channel; it is selectively permeable to various halide ions with the highest conductance to chloride, as well as allows various polyatomic anions to permeate such as nitrate and bicarbonate. ,− Nevertheless, it acts not only as an ion channel, but also as a regulator of other channels, such as exerting inhibitory activity on the epithelial sodium channel (ENaC). ,, …”

“…The CFTR protein is located predominantly on the epithelial cells of organs such as the pancreas, liver, salivary glands, gastrointestinal tract, lungs, and the male and female reproductive systems . Not restricted to these organs, CFTR is also detected to have regulatory functions in immunity; for instance, CFTR normal expression was found to impact various immune cell cytokine production and their normal functions. ,− Hence, CF patients not only exhibit abnormalities in organ functions but also experience immune dysregulation, such as chronic airway inflammation. , Besides, defective CFTR is often associated with a wide spectrum of comorbidities since it affects the viscosity and pH of mucus on the surface of multiple organs; the lung, pancreas, and GIT are the most frequently affected among CF patients. ,− …”

“…The CFTR protein is classified into the superfamily of ATP-binding cassette transporter ATPases based on its amino acid sequence. Unlike other common ATP-binding cassette transporter proteins, it functions as an ion channel rather than as a typical ATPase. , CFTR channels still exhibit the characteristic structure of the ATP-binding cassette protein superfamily . It is composed of five functional domains overall, two membrane spanning domains (MSDs) that form an ion transport pathway, two cytosolic nucleotide-binding domains (NBDs) which ATP binds to, and a cytosolic regulatory domain (R-domain) located between two MSDs, and needs to be phosphorylated by Protein Kinase A for CFTR to function effectively (Figure ).…”

Atribuição Do Canal CFTR Na Fibrose Cística

“…CFTR é uma glicoproteína contendo 1480 aminoácidos em sua estrutura (HANSSENS; DUCHATEAU; CASIMIR, 2021) com 5 domínios distintos, sendo que duas porções atravessam a membrana (MSD1, MSD2), duas porções fazem ligação com adenosina monofosfato (NBD1, NBD2) e uma porção denominada (R) sofre alteração em sua conformação e ativa o canal, promovendo o efluxo do íon Cl-, o que garante o funcionamento adequado do canal(LEE et al, 2021). A ativação é dependente de fosforilação, na qual atuam as proteínas quinases(FERNANDEZ et al, 2018), e o seu ajuste é feito pela adenosina trifosfato (ATP)(ANGYAL et al, 2021), essa fase, na qual a porção (R) sofre fosforilação é fundamental para que o canal se torne ativado(HWANG et al, 2018;LUKASIAK;ZAJAC, 2021).A FC foi mencionada pela primeira vez em 1930 (HANSSENS; DUCHATEAU; CASIMIR, 2021).É caracterizada com uma herança genética autossômica recessiva, relatada na literatura com mais de 2000 variantes, sendo a mais habitual a deleção de fenilalanina(LÓPEZ-VALDEZ et al, 2021) na posição 508 (COONEY; MCCRAY; Proteínas defeituosas são degradas no proteassoma (GENTZSCH; MALL, 2018), 88% possuem esse tipo de variação relacionado primordialmente com a fenilalanina na posição 508 (LEE et al, 2021). Quando ocorre o transporte adequado para a membrana apical, contudo, o canal não se abre de maneira correta a classe correspondente é a III (LÓPEZ-VALDEZ et al, 2021).…”