Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition.
Accumulation of unwanted/misfolded proteins in aggregates has been observed in airways of patients with cystic fibrosis (CF), a life-threatening genetic disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). Here we show how the defective CFTR results in defective autophagy and decreases the clearance ... of aggresomes. Defective CFTR-induced upregulation of reactive oxygen species (ROS) and tissue transglutaminase (TG2) drive the crosslinking of beclin 1, leading to sequestration of phosphatidylinositol-3-kinase (PI(3)K) complex III and accumulation of p62, which regulates aggresome formation. Both CFTR knockdown and the overexpression of green fluorescent protein (GFP)-tagged-CFTR(F508del) induce beclin 1 downregulation and defective autophagy in non-CF airway epithelia through the ROS-TG2 pathway. Restoration of beclin 1 and autophagy by either beclin 1 overexpression, cystamine or antioxidants rescues the localization of the beclin 1 interactome to the endoplasmic reticulum and reverts the CF airway phenotype in vitro, in vivo in Scnn1b-transgenic and Cftr(F508del) homozygous mice, and in human CF nasal biopsies. Restoring beclin 1 or knocking down p62 rescued the trafficking of CFTR(F508del) to the cell surface. These data link the CFTR defect to autophagy deficiency, leading to the accumulation of protein aggregates and to lung inflammation.
Mesh Terms:
Acetylcysteine, Adaptor Proteins, Signal Transducing, Adolescent, Adult, Animals, Antioxidants, Apoptosis Regulatory Proteins, Autophagy, Cell Line, Cystamine, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Epithelial Sodium Channels, Heat-Shock Proteins, Humans, Inflammation, Membrane Proteins, Mice, Mice, Inbred CFTR, Mice, Inbred Strains, Mice, Transgenic, Microtubule-Associated Proteins, Models, Biological, Nasal Polyps, Organometallic Compounds, Phosphatidylinositol 3-Kinases, Protein Binding, Protein Transport, Reactive Oxygen Species, Respiratory Mucosa, Salicylates, Small Ubiquitin-Related Modifier Proteins, Transglutaminases, Young Adult
Acetylcysteine, Adaptor Proteins, Signal Transducing, Adolescent, Adult, Animals, Antioxidants, Apoptosis Regulatory Proteins, Autophagy, Cell Line, Cystamine, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator, Epithelial Sodium Channels, Heat-Shock Proteins, Humans, Inflammation, Membrane Proteins, Mice, Mice, Inbred CFTR, Mice, Inbred Strains, Mice, Transgenic, Microtubule-Associated Proteins, Models, Biological, Nasal Polyps, Organometallic Compounds, Phosphatidylinositol 3-Kinases, Protein Binding, Protein Transport, Reactive Oxygen Species, Respiratory Mucosa, Salicylates, Small Ubiquitin-Related Modifier Proteins, Transglutaminases, Young Adult
Nat. Cell Biol.
Date: Sep. 01, 2010
PubMed ID: 20711182
View in: Pubmed Google Scholar
Download Curated Data For This Publication
164498
Switch View:
- Interactions 11
- PTM Genes 1