Mutations in the cystic fibrosis transmembrane conductance regulator protein (CFTR) often result in a failure of the protein to be properly processed at the level of the endoplasmic reticulum (ER) and subsequently transported to the plasma membrane. The folding defect associated with the most common CFTR mutation (delta F508) has been shown to be temperature sensitive. Incubation of cells expressing delta F508 CFTR at lower growth temperatures results in the proper processing of a portion of the mutant CFTR protein. Under these conditions, the mutant protein can move to the plasma membrane where it functions, similar to the wild-type protein, in mediating chloride transport. We set out to identify other methods, which like temperature treatment, would rescue the folding defect associated with the delta F508 CFTR mutation. Here we show that treatment of cells expressing the delta F508 mutant with a number of low molecular weight compounds, all known to stabilize proteins in their native conformation, results in the correct processing of the mutant CFTR protein and its deposition at the plasma membrane. Such compounds included the cellular osmolytes glycerol and trimethylamine N-oxide, as well as deuterated water. Treatment of the delta F508 CFTR-expressing cells with any one of these compounds, which we now refer to as 'chemical chaperones', restored the ability of the mutant cells to exhibit forskolin-dependent chloride transport, similar to that observed for the cells expressing the wild-type CFTR protein. We suggest that the use of 'chemical chaperones' may prove to be effective for the treatment of cystic fibrosis, as well as other genetic diseases whose underlying basis involves defective protein folding and/or a failure in normal protein trafficking events.
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http://dx.doi.org/10.1379/1466-1268(1996)001<0117:ccctmp>2.3.co;2 | DOI Listing |
Biochem Biophys Res Commun
November 2024
Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, Sanda, 669-1330, Hyogo, Japan. Electronic address:
The most common CFTR mutant in cystic fibrosis (CF), ΔF508 CFTR, is eliminated by ubiquitination even in the presence of CF drugs, reducing their therapeutic efficacy. RFFL is one of the ubiquitin ligases that remove ΔF508 CFTR from the cell surface despite treatment with the triple combination of CFTR modulators (TEZ/ELX/IVA) used clinically. Although RFFL knockdown has been shown to enhance the efficacy of TEZ/ELX/IVA in cell culture models, its impact in mouse models has not been evaluated.
View Article and Find Full Text PDFEur J Pharmacol
September 2024
Department of Pediatrics/Gastroenterology and Hepatology, Yale School of Medicine, New Haven, CT, USA; Department of Molecular Physiology, Yale School of Medicine, New Haven, CT, USA. Electronic address:
The CFTR modulator Trikafta has markedly improved lung disease for Cystic Fibrosis (CF) patients carrying the common delta F508 (F508del-CFTR) CFTR mutation. F508del-CFTR results in an apical trafficking defect and loss of function in CFTR-expressing epithelial cells. However, Trikafta has not resulted in improved gastrointestinal function in CF patients.
View Article and Find Full Text PDFEpidemiol Prev
May 2024
Unità Interdipartimentale Malattie Rare Senza Diagnosi, Centro Nazionale Malattie Rare, Istituto Superiore di Sanità, Roma.
Introduction: Italian Cystic Fibrosis Registry (ICFR) collects data of patients with cystic fibrosis (CF) through the collaboration with Italian CF referral and support Centres (Italian law 548/93). It aims at analysing medium and long-term clinical and epidemiological trends, identifying healthcare needs at regional and national levels, contributing to healthcare programmes, and resource allocation. Italian data are also compared at international level through the collaboration with the European CF Registry for sharing epidemiological data on general aspects like CF epidemiology and specific topics such as the use of CFTR modulators.
View Article and Find Full Text PDFPediatr Pulmonol
September 2023
Perth Children's Hospital, Nedlands, Western Australia, Australia.
Background: Tracheobronchomalacia (TBM) is estimated to be present in 1 in 2100 children. Previous reports suggest the prevalence is higher in children with cystic fibrosis (CF). This has clinical implications with potential to influence airway clearance and lung health.
View Article and Find Full Text PDFNutrients
October 2022
Institute of Physiological Chemistry and Pathobiochemistry, Muenster University Hospital, Waldeyerstr. 15, 48129 Muenster, Germany.
Treatment of cystic fibrosis relies so far on expensive and sophisticated drugs. A logical approach to rescuing the defective ΔF508-CFTR protein has not yet been published. Therefore, virtual docking of ATP and CFTR activators to the open conformation of the CFTR protein was performed.
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