Cystic fibrosis: a disorder with defective autophagy.
The accumulation of misfolded and/or ubiquitinated protein aggregates with a perturbation of autophagy has been described in several human pathologies. A sequestration of misfolded cystic: fibrosis transmembrane conductance regulator (CFTR) and cross-linked PPARγ has been observed in airway epithelia of cystic fibrosis (CF) patients. CF airways are also characterized by chronic inflammation, pro-oxidative environment and increased transglutaminase 2 (TG2) levels. We showed that defective CFTR drives autophagy inhibition through reactive oxygen species (ROS)-TG2- mediated aggresome sequestration of the Beclin 1 interactome. Rescuing Beclin 1 at the level of the endoplasmic reticulum and autophagy favors clearance of aggresomes, improves CFTR trafficking and ameliorates CF lung inflammation both in vitro and in vivo. Therefore, rescuing autophagy interrupts the vicious cycle linking defective CFTR and lung inflammation and may pave the way to the development of a novel class of drugs for the treatment of CF.
European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Milan, Italy.
Alessandro
A
Luciani
Valeria R
VR
Villella
Speranza
S
Esposito
Nicola
N
Brunetti-Pierri
Diego L
DL
Medina
Carmine
C
Settembre
Manuela
M
Gavina
Valeria
V
Raia
Andrea
A
Ballabio
Luigi
L
Maiuri
D000818:Animals; D001343:Autophagy; D003550:Cystic Fibrosis / Q000201:enzymology / Q000473:pathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D017382:Reactive Oxygen Species / Q000378:metabolism; D011503:Transglutaminases / Q000378:metabolism
D017382:Reactive Oxygen Species; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins