Chest
Recent Advances in Chest MedicineCystic Fibrosis Transmembrane Conductance Regulator Intracellular Processing, Trafficking, and Opportunities for Mutation-Specific Treatment
Section snippets
CFTR Molecular Biology and Cellular Quality Control
The CFTR gene, comprising 180,000 base pairs, is located on the long arm of chromosome 7 and encodes a 1,480-amino acid membrane protein. The wild-type CFTR glycoprotein localizes in the apical plasma membrane and functions as a regulated chloride channel. CFTR might also affect bicarbonate-chloride exchange plus sodium and water transport in secretory and resorptive epithelium.3, 4 CFTR is a member of the large adenosine triphosphate (ATP)-binding cassette (ABC) transporter protein family. ABC
Correctors of Trafficking, Potentiators of Function, and Overcoming Premature Termination Codons
F508del, the missense mutation causing a phenylalanine deletion at position 508 in the CFTR protein, accounts for approximately 70% of all CF alleles and is found in up to 90% of patients with CF in some populations.45, 46 In addition to the high frequency of the F508del mutation, two other facts make corrective and potentiating therapies strategically relevant. First, F508del-CFTR retains function (albeit reduced relative to wild-type CFTR) when delivered to the apical plasma membrane.29, 47,
Five Classes of Defective CFTR Protein Processing Based on Gene Mutation
Although > 1,500 mutations of CFTR have been identified, only four specific mutations besides F508del reach a frequency of 1% to 3%: G551D, W1282X, G542X, and N1303K. In fact, only about 20 specific mutations reach a threshold frequency > 0.1% (Cystic Fibrosis Genetic Analysis Consortium database, www.genet.sickkids.on.ca/cftr). Specific mutations appear to be enriched within ethnic groups.53 For example, the nonsense mutation, W1282X (a PTC in place of tryptophan residue 1282) accounts for
Phenotypic Variation
When considering a uniformly homozygous F508del population, in general, the phenotype is severe, exhibiting pancreatic insufficiency and relentless progressive bronchiectasis. However, significant numbers of outliers with variable clinical severity exist. Variation can be attributed to the environment, the quantity of retained CFTR function, adherence to therapies, and genetic modifiers.63 Environmental variables include the advent of coordinated multidisciplinary CF care and enhanced mucous
Mutation Class and Prognostication
Certain generalizations about variable organ dysfunction traditionally have been linked to genotype severity. For example, almost all men with CF are infertile and, thus, the vas deferens generally are believed to be the most sensitive human organ to the CF genotype. Similarly, CF-related liver disease, exocrine pancreatic insufficiency, and malnutrition are more common in nonfunctional CFTR mutations. The pancreas, however, is somewhat less sensitive to loss of CFTR function. Individuals with
Progress Toward Mutation-Specific Modifier Treatments
Most of the current therapeutic strategies in use for CF involve treatments that alleviate symptoms and complications that result from loss of CFTR function, and consensus statements detailing these therapies have been published recently.68, 69 On the cutting edge of CF treatment, gene therapy continues to be pursued aggressively as evidenced by > 200 gene therapy trials undertaken since the 1990s. To date, effective and meaningful clinical outcomes remain elusive, and no gene therapies have
Concluding Perspectives
Mutation-specific treatments hold promise for finally answering the question that has been lingering since and even before the CFTR gene discovery: Will therapies that specifically restore CFTR-mediated chloride secretion slow or arrest the deleterious cascade of events leading to chronic infection, bronchiectasis, and end-stage lung disease? The successes reported from early phase trials translating mutation-specific approaches into measurable patient outcomes have created much excitement, and
Acknowledgments
Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Hornick has participated in enrolling patients in early phase clinical trials of Vertex Pharmaceuticals products and has participated in the writing of manuscripts and abstracts describing results of studies. Drs Rogan and Stoltz have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Role
References (112)
Cystic fibrosis: impaired bicarbonate secretion and mucoviscidosis
Lancet
(2008)- et al.
Intracellular turnover of cystic fibrosis transmembrane conductance regulator. Inefficient processing and rapid degradation of wild-type and mutant proteins
J Biol Chem
(1994) - et al.
Degradation of CFTR by the ubiquitin-proteasome pathway
Cell
(1995) - et al.
Sequential quality-control checkpoints triage misfolded cystic fibrosis transmembrane conductance regulator
Cell
(2006) - et al.
A principal role for the proteasome in endoplasmic reticulum-associated degradation of misfolded intracellular cystic fibrosis transmembrane conductance regulator
J Biol Chem
(2002) - et al.
Calreticulin negatively regulates the cell surface expression of cystic fibrosis transmembrane conductance regulator
J Biol Chem
(2006) - et al.
Derlin-1 promotes the efficient degradation of the cystic fibrosis transmembrane conductance regulator (CFTR) and CFTR folding mutants
J Biol Chem
(2006) - et al.
Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis
Cell
(2006) - et al.
Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis
Cell
(1990) - et al.
The delta F508 mutation decreases the stability of cystic fibrosis transmembrane conductance regulator in the plasma membrane. Determination of functional half-lives on transfected cells
J Biol Chem
(1993)
The short apical membrane half-life of rescued DeltaF508-cystic fibrosis transmembrane conductance regulator (CFTR) results from accelerated endocytosis of DeltaF508-CFTR in polarized human airway epithelial cells
J Biol Chem
Nucleoside triphosphates are required to open the CFTR chloride channel
Cell
Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice
J Cyst Fibros
Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis
Cell
Correlation of sweat chloride concentration with classes of the cystic fibrosis transmembrane conductance regulator gene mutations
J Pediatr
Structural biology of Rad50 ATPase: ATP-driven conformational control in DNA double-strand break repair and the ABC-ATPase superfamily
Cell
CFTR genotype as a predictor of prognosis in cystic fibrosis
Chest
Cystic fibrosis adult care: consensus conference report
Chest
Gene therapy in cystic fibrosis
Chest
Green fluorescent protein-based halide indicators with improved chloride and iodide affinities
FEBS Lett
Novel CFTR chloride channel activators identified by screening of combinatorial libraries based on flavone and benzoquinolizinium lead compounds
J Biol Chem
Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial
Lancet
Correctors promote maturation of cystic fibrosis transmembrane conductance regulator (CFTR)-processing mutants by binding to the protein
J Biol Chem
Glycerol reverses the misfolding phenotype of the most common cystic fibrosis mutation
J Biol Chem
A set of endoplasmic reticulum proteins possessing properties of molecular chaperones includes Ca(2+)-binding proteins and members of the thioredoxin superfamily
J Biol Chem
Evidence of CFTR function in cystic fibrosis after systemic administration of 4-phenylbutyrate
Mol Ther
Cystic fibrosis
Cystic fibrosis
Am J Respir Crit Care Med
Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA
Science
CFTR function and prospects for therapy
Annu Rev Biochem
Cystic fibrosis: premature degradation of mutant proteins as a molecular disease mechanism
Methods Mol Biol
Conformational maturation of CFTR but not its mutant counterpart (delta F508) occurs in the endoplasmic reticulum and requires ATP
EMBO J
Misfolding of the cystic fibrosis transmembrane conductance regulator and disease
Biochemistry
The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation
Nat Cell Biol
A foldable CFTRDeltaF508 biogenic intermediate accumulates upon inhibition of the Hsc70-CHIP E3 ubiquitin ligase
J Cell Biol
The role of the UPS in cystic fibrosis
BMC Biochem
The ubiquitin proteasome system in Huntington's disease and the spinocerebellar ataxias
BMC Biochem
Assembly and misassembly of cystic fibrosis transmembrane conductance regulator: folding defects caused by deletion of F508 occur before and after the calnexin-dependent association of membrane spanning domain (MSD) 1 and MSD2
Mol Biol Cell
Cystic fibrosis transmembrane conductance regulator degradation depends on the lectins Htm1p/EDEM and the Cdc48 protein complex in yeast
Mol Biol Cell
The cochaperone HspBP1 inhibits the CHIP ubiquitin ligase and stimulates the maturation of the cystic fibrosis transmembrane conductance regulator
Mol Biol Cell
Chaperone displacement from mutant cystic fibrosis transmembrane conductance regulator restores its function in human airway epithelia
FASEB J
N-glycans are direct determinants of CFTR folding and stability in secretory and endocytic membrane traffic
J Cell Biol
COPII-dependent export of cystic fibrosis transmembrane conductance regulator from the ER uses a di-acidic exit code
J Cell Biol
Inhibiting endoplasmic reticulum (ER)-associated degradation of misfolded Yor1p does not permit ER export despite the presence of a diacidic sorting signal
Mol Biol Cell
Biological and structural basis for Aha1 regulation of Hsp90 ATPase activity in maintaining proteostasis in the human disease cystic fibrosis
Mol Biol Cell
Adapting proteostasis for disease intervention
Science
Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive
Nature
Constitutive internalization of cystic fibrosis transmembrane conductance regulator occurs via clathrin-dependent endocytosis and is regulated by protein phosphorylation
Biochem J
Misfolding diverts CFTR from recycling to degradation: quality control at early endosomes
J Cell Biol
Peripheral protein quality control removes unfolded CFTR from the plasma membrane
Science
Cited by (120)
Potential systemic effects of acquired CFTR dysfunction in COPD
2024, Respiratory MedicineMolecular diagnosis of cystic fibrosis
2023, Diagnostic Molecular Pathology: A Guide to Applied Molecular Testing, Second EditionApplications of CRISPR as a potential therapeutic
2021, Life SciencesIn silico drug repositioning on F508del-CFTR: A proof-of-concept study on the AIFA library
2021, European Journal of Medicinal ChemistrySpecificity in PDZ-peptide interaction networks: Computational analysis and review
2020, Journal of Structural Biology: X
Funding/Support: Dr Hornick is supported in part by the Cystic Fibrosis Foundation Translational Center Grant, which included funding to participate in industry-sponsored (eg, PTC Therapeutics, Vertex Pharmaceuticals) clinical trials.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).