Processing and function of CFTR-ΔF508 are species-dependent
- 25 September 2007
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 104 (39), 15370-15375
- https://doi.org/10.1073/pnas.0706974104
Abstract
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis. The most common mutation, a deletion of the phenylalanine at position 508 (DeltaF508), disrupts processing of the protein. Nearly all human CFTR-DeltaF508 is retained in the endoplasmic reticulum and degraded, preventing maturation to the plasma membrane. In addition, the F508 deletion reduces the activity of single CFTR channels. Human CFTR-DeltaF508 has been extensively studied to better understand its defects. Here, we adopted a cross-species comparative approach, examining human, pig, and mouse CFTR-DeltaF508. As with human CFTR-DeltaF508, the DeltaF508 mutation reduced the single-channel activity of the pig and mouse channels. However, the mutant pig and mouse proteins were at least partially processed like their wild-type counterparts. Moreover, pig and mouse CFTR-DeltaF508 partially restored transepithelial Cl(-) transport to CF airway epithelia. Our data, combined with earlier work, suggest that there is a gradient in the severity of the CFTR-DeltaF508 processing defect, with human more severe than pig or mouse. These findings may explain some previously puzzling observations in CF mice, they have important implications for evaluation of potential therapeutics, and they suggest new strategies for discovering the mechanisms that disrupt processing of human CFTR-DeltaF508.Keywords
This publication has 65 references indexed in Scilit:
- Bioelectric Properties of Chloride Channels in Human, Pig, Ferret, and Mouse Airway EpitheliaAmerican Journal of Respiratory Cell and Molecular Biology, 2007
- Revertant mutants G550E and 4RK rescue cystic fibrosis mutants in the first nucleotide-binding domain of CFTR by different mechanismsProceedings of the National Academy of Sciences of the United States of America, 2006
- Rescue of ΔF508-CFTR trafficking and gating in human cystic fibrosis airway primary cultures by small moleculesAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2006
- Small-molecule correctors of defective F508-CFTR cellular processing identified by high-throughput screeningJCI Insight, 2005
- Processing of CFTR: Traversing the cellular maze—How much CFTR needs to go through to avoid cystic fibrosis?Pediatric Pulmonology, 2005
- Regulated trafficking of the CFTR chloride channelEuropean Journal of Cell Biology, 2000
- Defects in processing and trafficking of the cystic fibrosis transmembrane conductance regulatorKidney International, 2000
- Comparison of the gating behaviour of human and murine cystic fibrosis transmembrane conductance regulator Cl− channels expressed in mammalian cellsThe Journal of Physiology, 1998
- A delta F508 mutation in mouse cystic fibrosis transmembrane conductance regulator results in a temperature-sensitive processing defect in vivo.JCI Insight, 1996
- Glycerol Reverses the Misfolding Phenotype of the Most Common Cystic Fibrosis MutationJournal of Biological Chemistry, 1996