C. W. Valle and N. Vij Pages 860 - 871 ( 12 )
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.
ΔF508, CFTR, cystic fibrosis, ERAD, proteasome, proteostasis, therapeutics, ubiquitin, conformation, protein synthesis, neurodegenerative diseases, cardiovascular diseases, autosomal recessive disorders, mutation, ion transport
, Department of Pediatrics & Institute of NanoBiotechnology, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, CMSC 3-122, Baltimore, MD 21287, USA.