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

Membranes ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 804
Author(s):  
Agnieszka Lukasiak ◽  
Miroslaw Zajac
Keyword(s):  
Cystic Fibrosis ◽  
Physiological Role ◽  
Anion Channel ◽  
Fluid Secretion ◽  
Hereditary Disease ◽  
Gene Encoding ◽  
Pharmacological Agents ◽  
Intracellular Compartments ◽  
Cftr Protein

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.

scholarly journals A Developmental Role of the Cystic Fibrosis Transmembrane Conductance Regulator in Cystic Fibrosis Lung Disease Pathogenesis

2021 ◽  
Vol 9 ◽  
Author(s):  
Elena N. Huang ◽  
Henry Quach ◽  
Jin-A Lee ◽  
Joshua Dierolf ◽  
Theo J. Moraes ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Anion Channel ◽  
Airway Disease ◽  
Genetic Mutation ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Disease Pathogenesis ◽  
Cftr Protein

The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein is a cAMP-activated anion channel that is critical for regulating fluid and ion transport across the epithelium. This process is disrupted in CF epithelia, and patients harbouring CF-causing mutations experience reduced lung function as a result, associated with the increased rate of mortality. Much progress has been made in CF research leading to treatments that improve CFTR function, including small molecule modulators. However, clinical outcomes are not necessarily mutation-specific as individuals harboring the same genetic mutation may present with varying disease manifestations and responses to therapy. This suggests that the CFTR protein may have alternative functions that remain under-appreciated and yet can impact disease. In this mini review, we highlight some notable research implicating an important role of CFTR protein during early lung development and how mutant CFTR proteins may impact CF airway disease pathogenesis. We also discuss recent novel cell and animal models that can now be used to identify a developmental cause of CF lung disease.

scholarly journals GM1 as Adjuvant of Innovative Therapies for Cystic Fibrosis Disease

2020 ◽  
Vol 21 (12) ◽  
pp. 4486 ◽  
Author(s):  
Giulia Mancini ◽  
Nicoletta Loberto ◽  
Debora Olioso ◽  
Maria Cristina Dechecchi ◽  
Giulio Cabrini ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Anion Channel ◽  
Apical Plasma Membrane ◽  
Multiple Drug ◽  
Common Mutation ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Starting Point ◽  
Innovative Therapies ◽  
Cftr Protein

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein is expressed at the apical plasma membrane (PM) of different epithelial cells. The most common mutation responsible for the onset of cystic fibrosis (CF), F508del, inhibits the biosynthesis and transport of the protein at PM, and also presents gating and stability defects of the membrane anion channel upon its rescue by the use of correctors and potentiators. This prompted a multiple drug strategy for F508delCFTR aimed simultaneously at its rescue, functional potentiation and PM stabilization. Since ganglioside GM1 is involved in the functional stabilization of transmembrane proteins, we investigated its role as an adjuvant to increase the effectiveness of CFTR modulators. According to our results, we found that GM1 resides in the same PM microenvironment as CFTR. In CF cells, the expression of the mutated channel is accompanied by a decrease in the PM GM1 content. Interestingly, by the exogenous administration of GM1, it becomes a component of the PM, reducing the destabilizing effect of the potentiator VX-770 on rescued CFTR protein expression/function and improving its stabilization. This evidence could represent a starting point for developing innovative therapeutic strategies based on the co-administration of GM1, correctors and potentiators, with the aim of improving F508del CFTR function.

scholarly journals Deletion of the rpoZ gene, encoding the ω subunit of RNA polymerase, results in pleiotropic surface-related phenotypes in Mycobacterium smegmatis

Microbiology ◽  
2006 ◽  
Vol 152 (6) ◽  
pp. 1741-1750 ◽  
Author(s):  
Renjith Mathew ◽  
Raju Mukherjee ◽  
Radhakrishnan Balachandar ◽  
Dipankar Chatterji
Keyword(s):  
Rna Polymerase ◽  
Mycobacterium Smegmatis ◽  
Biofilm Formation ◽  
Physiological Role ◽  
Wild Type ◽  
Gene Encoding ◽  
Biofilm Growth ◽  
Mutant Bacterium ◽  
Sliding Motility

The ω subunit, the smallest subunit of bacterial RNA polymerase, is known to be involved in maintaining the conformation of the β′ subunit and aiding its recruitment to the rest of the core enzyme assembly in Escherichia coli. It has recently been shown in Mycobacterium smegmatis, by creating a deletion mutation of the rpoZ gene encoding ω, that the physiological role of the ω subunit also includes providing physical protection to β′. Interestingly, the mutant had altered colony morphology. This paper demonstrates that the mutant mycobacterium has pleiotropic phenotypes including reduced sliding motility and defective biofilm formation. Analysis of the spatial arrangement of biofilms by electron microscopy suggests that the altered phenotype of the mutant arises from a deficiency in generation of extracellular matrix. Complementation of the mutant strain with a copy of the wild-type rpoZ gene integrated in the bacterial chromosome restored both sliding motility and biofilm formation to the wild-type state, unequivocally proving the role of ω in the characteristics observed for the mutant bacterium. Analysis of the cell wall composition demonstrated that the mutant bacterium had an identical glycopeptidolipid profile to the wild-type, but failed to synthesize the short-chain mycolic acids characteristic of biofilm growth in M. smegmatis.

scholarly journals The combination of tezacaftor and ivacaftor in the treatment of patients with cystic fibrosis: clinical evidence and future prospects in cystic fibrosis therapy

2019 ◽  
Vol 13 ◽  
pp. 175346661984442 ◽  
Author(s):  
Sherstin T. Lommatzsch ◽  
Jennifer L. Taylor-Cousar
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Evidence ◽  
Anion Channel ◽  
The United States ◽  
New Era ◽  
Sweat Chloride ◽  
Cftr Protein ◽  
Surface Liquid ◽  
Cftr Modulators ◽  
Epithelial Sodium Channel Enac

Years of tremendous study have dawned a new era for the treatment of cystic fibrosis (CF). For years CF care was rooted in the management of organ dysfunction resulting from the mal-effects of absent anion transport through the CF transmembrane regulator (CFTR) protein. CFTR, an adenosine triphosphate binding anion channel, has multiple functions, but primarily regulates the movement of chloride anions, thiocyanate and bicarbonate across luminal cell membranes. Additional roles include effects on other electrolyte channels such as the epithelial sodium channel (ENaC) and on pulmonary innate immunity. Inappropriate luminal anion movement leads to elevated sweat chloride concentrations, dehydrated airway surface liquid, overall viscous mucous production, and inspissated bile and pancreatic secretions. As a result, patients develop the well-known CF symptoms and disease-defining complications such as chronic cough, oily stools, recurrent pulmonary infections, bronchiectasis, chronic sinusitis and malnutrition. Traditionally, CF has been symptomatically managed, but over the past 6 years those with CF have been offered a new mode of therapy; CFTR protein modulation. These medications affect the basic defect in CF: abnormal CFTR function. Ivacaftor, approved for use in the United States in 2012, is the first medication in CF history to improve CFTR function at the molecular level. Its study and approval were followed by two additional CFTR modulators, lumacaftor/ivacaftor and tezacaftor/ivacaftor. To effectively use currently available CF therapies, clinicians should be familiar with the side effects of the drugs and their impacts on patient outcomes. As many new modulators are on the horizon, this information will equip providers to discuss the benefits and shortcomings of modulator therapy especially in the context of limited healthcare resources.

scholarly journals Cytoskeleton regulators CAPZA2 and INF2 associate with CFTR to control its plasma membrane levels under EPAC1 activation

2020 ◽  
Vol 477 (13) ◽  
pp. 2561-2580
Author(s):  
João D. Santos ◽  
Francisco R. Pinto ◽  
João F. Ferreira ◽  
Margarida D. Amaral ◽  
Manuela Zaccolo ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Protein A ◽  
Bioinformatic Analysis ◽  
Apical Surface ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Gene Encoding ◽  
Cftr Protein ◽  
Related Proteins ◽  
Cystic Fibrosis Transmembrane

Cystic Fibrosis (CF), the most common lethal autosomic recessive disorder among Caucasians, is caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein, a cAMP-regulated chloride channel expressed at the apical surface of epithelial cells. Cyclic AMP regulates both CFTR channel gating through a protein kinase A (PKA)-dependent process and plasma membane (PM) stability through activation of the exchange protein directly activated by cAMP1 (EPAC1). This cAMP effector, when activated promotes the NHERF1:CFTR interaction leading to an increase in CFTR at the PM by decreasing its endocytosis. Here, we used protein interaction profiling and bioinformatic analysis to identify proteins that interact with CFTR under EPAC1 activation as possible regulators of this CFTR PM anchoring. We identified an enrichment in cytoskeleton related proteins among which we characterized CAPZA2 and INF2 as regulators of CFTR trafficking to the PM. We found that CAPZA2 promotes wt-CFTR trafficking under EPAC1 activation at the PM whereas reduction of INF2 levels leads to a similar trafficking promotion effect. These results suggest that CAPZA2 is a positive regulator and INF2 a negative one for the increase of CFTR at the PM after an increase of cAMP and concomitant EPAC1 activation. Identifying the specific interactions involving CFTR and elicited by EPAC1 activation provides novel insights into late CFTR trafficking, insertion and/or stabilization at the PM and highlighs new potential therapeutic targets to tackle CF disease.

scholarly journals Bicarbonate Transport in Cystic Fibrosis and Pancreatitis

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 54
Author(s):  
Dora Angyal ◽  
Marcel J. C. Bijvelds ◽  
Marco J. Bruno ◽  
Maikel P. Peppelenbosch ◽  
Hugo R. de Jonge
Keyword(s):  
Cystic Fibrosis ◽  
Current Knowledge ◽  
Pancreatic Insufficiency ◽  
Anion Channel ◽  
Exocrine Pancreatic Insufficiency ◽  
Scaffolding Protein ◽  
Bicarbonate Transport ◽  
Human Pancreas ◽  
Ductal Cells

CFTR, the cystic fibrosis (CF) gene-encoded epithelial anion channel, has a prominent role in driving chloride, bicarbonate and fluid secretion in the ductal cells of the exocrine pancreas. Whereas severe mutations in CFTR cause fibrosis of the pancreas in utero, CFTR mutants with residual function, or CFTR variants with a normal chloride but defective bicarbonate permeability (CFTRBD), are associated with an enhanced risk of pancreatitis. Recent studies indicate that CFTR function is not only compromised in genetic but also in selected patients with an acquired form of pancreatitis induced by alcohol, bile salts or smoking. In this review, we summarize recent insights into the mechanism and regulation of CFTR-mediated and modulated bicarbonate secretion in the pancreatic duct, including the role of the osmotic stress/chloride sensor WNK1 and the scaffolding protein IRBIT, and current knowledge about the role of CFTR in genetic and acquired forms of pancreatitis. Furthermore, we discuss the perspectives for CFTR modulator therapy in the treatment of exocrine pancreatic insufficiency and pancreatitis and introduce pancreatic organoids as a promising model system to study CFTR function in the human pancreas, its role in the pathology of pancreatitis and its sensitivity to CFTR modulators on a personalized basis.

scholarly journals Progress Toward The Synthesis Of Labeled Derivatives Of The Cystic Fibrosis Drug Ivacaftor

2021 ◽  
Author(s):  
Salma Elmallah
Keyword(s):  
Cystic Fibrosis ◽  
Plasma Membrane ◽  
Genetic Diseases ◽  
Early Death ◽  
Open Probability ◽  
Gene Encoding ◽  
Short Period ◽  
Cftr Mutations ◽  
Cftr Protein ◽  
Orally Bioavailable

Cystic fibrosis (CF) is one of the most common genetic diseases, affecting approximately 70,000 people worldwide causing severe complications and often leading to early death. CF is caused by a mutation in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein which is responsible for fluid and ion transport through epithelial membranes maintaining the formation of a thin slippery mucous layer. CFTR mutations either lead to a trafficking defect where the CFTR protein does not reach the plasma membrane or a gating defect where CFTR protein at the plasma membrane does not function properly. Treatment of cystic fibrosis usually addresses the symptoms to overcome the complications of the disease such as pneumonia, lung infections, pancreatitis, maldigestion and infertility. Vertex pharmaceuticals has been interested in developing small molecules that have the ability to interact with mutated CFTR proteins, aiding in their delivery to the cell membrane and/or restoring their channel function. VX-770 is an orally bioavailable potentiator that has the ability to improve the gating activity and increasing the open probability of CFTR protein in patients carrying the G551D mutation. VX770, Ivacaftor, was recently approved by the US FDA after showing very good improvements in the lung function in CF patients with good safety profile. Our research is focusing on the synthesis of VX770 under mild conditions and formation of labeled derivatives to help in the understanding of its exact mode of action. Different methods were developed toward the synthesis of the two main components, LHS and RHS, of VX770 by using less harsh conditions for a short period of time. We were successfully able to make two photoaffinity labeled derivatives, aryl azide and benzophenone derivatives, which will be beneficial in tracking the drug molecule and revealing the exact site of interaction between the drug and the protein. Synthesis of VX770 fragments was is another focus of interest in our research as they will provide us with information about the best positions for further derivatization.

scholarly journals Regulation and Physiological Role of theDAS1 Gene, Encoding Dihydroxyacetone Synthase, in the Methylotrophic Yeast Candida boidinii

1998 ◽  
Vol 180 (22) ◽  
pp. 5885-5890 ◽  
Author(s):  
Yasuyoshi Sakai ◽  
Tomoyuki Nakagawa ◽  
Masayuki Shimase ◽  
Nobuo Kato
Keyword(s):  
Formate Dehydrogenase ◽  
Physiological Role ◽  
Nitrogen Sources ◽  
Host Genome ◽  
Candida Boidinii ◽  
Carbon And Nitrogen Sources ◽  
Gene Encoding ◽  
Carbon And Nitrogen ◽  
Dihydroxyacetone Synthase

ABSTRACT The physiological role of dihydroxyacetone synthase (DHAS) inCandida boidinii was evaluated at the molecular level. TheDAS1 gene, encoding DHAS, was cloned from the host genome, and regulation of its expression by various carbon and nitrogen sources was analyzed. Western and Northern analyses revealed thatDAS1 expression was regulated mainly at the mRNA level. The regulatory pattern of DHAS was similar to that of alcohol oxidase but distinct from that of two other enzymes in the formaldehyde dissimilation pathway, glutathione-dependent formaldehyde dehydrogenase and formate dehydrogenase. The DAS1 gene was disrupted in one step in the host genome (das1Δ strain), and the growth of the das1Δ strain in various carbon and nitrogen sources was compared with that of the wild-type strain. Thedas1Δ strain had completely lost the ability to grow on methanol, while the strain with a disruption of the formate dehydrogenase gene could survive (Y. Sakai et al., J. Bacteriol. 179:4480–4485, 1997). These and other experiments (e.g., those to determine the expression of the gene and the growth ability of thedas1Δ strain on media containing methylamine or choline as a nitrogen source) suggested that DAS1 is involved in assimilation rather than dissimilation or detoxification of formaldehyde in the cells.

scholarly journals Impact of Altered Gut Microbiota and Its Metabolites in Cystic Fibrosis

Metabolites ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 123
Author(s):  
Aravind Thavamani ◽  
Iman Salem ◽  
Thomas J. Sferra ◽  
Senthilkumar Sankararaman
Keyword(s):  
Cystic Fibrosis ◽  
Genetic Disorder ◽  
Vital Role ◽  
Immune Functions ◽  
Gene Encoding ◽  
Gut Dysbiosis ◽  
Multiple Organs ◽  
Fluid Regulation ◽  
Cftr Protein ◽  
Cystic Fibrosis Transmembrane

Cystic fibrosis (CF) is the most common lethal, multisystemic genetic disorder in Caucasians. Mutations in the gene encoding the cystic fibrosis transmembrane regulator (CFTR) protein are responsible for impairment of epithelial anionic transport, leading to impaired fluid regulation and pH imbalance across multiple organs. Gastrointestinal (GI) manifestations in CF may begin in utero and continue throughout the life, resulting in a chronic state of an altered intestinal milieu. Inherent dysfunction of CFTR leads to dysbiosis of the gut. This state of dysbiosis is further perpetuated by acquired factors such as use of antibiotics for recurrent pulmonary exacerbations. Since the gastrointestinal microbiome and their metabolites play a vital role in nutrition, metabolic, inflammatory, and immune functions, the gut dysbiosis will in turn impact various manifestations of CF—both GI and extra-GI. This review focuses on the consequences of gut dysbiosis and its metabolic implications on CF disease and possible ways to restore homeostasis.

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