Can Correcting the ΔF508-CFTR Proteostasis-Defect Rescue CF Lung Disease?
C. W. Valle and N. Vij
Affiliation: Department of Pediatrics & Institute of NanoBiotechnology, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, CMSC 3-122, Baltimore, MD 21287, USA.
Protein homeostasis (proteostasis) generates and maintains individual proteins in their folded and
functional-competent states. The components of the cellular proteostasis machinery also dictate the functional
lifetime of a protein by constantly regulating its conformation, concentration and subcellular location. The
autosomal recessive disease cystic fibrosis (CF) is caused by a proteostasis-defect in CF transmembrane
conductance regulator (CFTR). The most common CF mutation leading to this proteostasis-defect is the
deletion of a phenylalanine residue at position 508 (ΔF508) of the CFTR protein. This ΔF508-CFTR protein is
prone to aberrant folding, increased ER-associated degradation, atypical intracellular trafficking and reduced
stability at the apical membrane. This ΔF508-CF proteostasis-defect leads to an obstructive lung disease
characterized by impaired ion transport in airway epithelial cells, mucus buildup in air space and chronic airway
inflammation. We assess here whether correcting the underlying defect in ΔF508-CFTR protein processing
using therapeutic proteostasis regulators can treat chronic CF lung disease. As a proof of concept, recent
studies support that the selective modulation of mutant-CFTR proteostasis may offer promising therapies to
reverse chronic CF lung disease.
Keywords: ΔF508, CFTR, cystic fibrosis, ERAD, proteasome, proteostasis, therapeutics, ubiquitin, conformation, protein synthesis, neurodegenerative diseases, cardiovascular diseases, autosomal recessive disorders, mutation, ion transport
Rights & PermissionsPrintExport