title: Protein processing and inflammatory signaling in Cystic Fibrosis: challenges and therapeutic strategies.
abstract: Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) that regulates epithelial surface fluid secretion in respiratory and gastrointestinal tracts. The deletion of phenylalanine at position 508 (DeltaF508) in CFTR is the most common mutation that results in a temperature sensitive folding defect, retention of the protein in the endoplasmic reticulum (ER), and subsequent degradation by the proteasome. ER associated degradation (ERAD) is a major quality control pathway of the cell. The majority (99%) of the protein folding, DeltaF508-, mutant of CFTR is known to be degraded by this pathway to cause CF. Recent studies have revealed that inhibition of DeltaF508-CFTR ubiquitination and proteasomal degradation can increase its cell surface expression and may provide an approach to treat CF. The finely tuned balance of ER membrane interactions determine the cytosolic fate of newly synthesized CFTR. These ER membrane interactions induce ubiquitination and proteasomal targeting of DeltaF508- over wild type- CFTR. We discuss here challenges and therapeutic strategies targeting protein processing of DeltaF508-CFTR with the goal of rescuing functional DeltaF508-CFTR to the cell surface. It is evident from recent studies that CFTR plays a critical role in inflammatory response in addition to its well-described ion transport function. Previous studies in CF have focused only on improving chloride efflux as a marker for promising treatment. We propose that methods quantifying the therapeutic efficacy and recovery from CF should not include only changes in chloride efflux, but also recovery of the chronic inflammatory signaling, as evidenced by positive changes in inflammatory markers (in vitro and ex vivo), lung function (pulmonary function tests, PFT), and chronic lung disease (state of the art molecular imaging, in vivo). This will provide novel therapeutics with greater opportunities of potentially attenuating the progression of the chronic CF lung disease.
authors.affiliation: Department of Pediatrics, Eudowood Division of Pulmonary Medicine, The Johns Hopkins University School of Medicine, Baltimore MD 21287, USA.
authors.forename: C N
authors.initials: CN
authors.lastname: Belcher
authors.forename: N
authors.initials: N
authors.lastname: Vij
mesh_terms: D000818:Animals; D003550:Cystic Fibrosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000473:pathology; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction
chemical_list: C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator