title: DeltaF508-CFTR causes constitutive NF-kappaB activation through an ER-overload response in cystic fibrosis lungs.
abstract: The clinical course of Cystic Fibrosis is characterized by recurrent pulmonary infections which ultimately lead to death by respiratory failure. The most common CF causing mutation, deltaF508-CFTR, produces an incorrectly folded protein, which accumulates within the endoplasmic reticulum. However, the molecular mechanism by which the deltaF508-CFTR protein facilitates pulmonary infection and inflammation remains unclear. Here we show that the expression of deltaF508-CFTR causes a constitutive activation of the pro-inflammatory transcription factor NF-kappaB by eliciting an ER stress reaction, the ER-overload response. This endogenous NF-kappaB activation stimulates the transcription of pro-inflammatory cytokines thereby commencing an inflammatory cascade within the CF lung.
authors.affiliation: Department of Experimental Anaesthesiology, University Hospital Freiburg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Knorre
authors.forename: Mathias
authors.initials: M
authors.lastname: Wagner
authors.forename: Hans-Eckart
authors.initials: HE
authors.lastname: Schaefer
authors.forename: William H
authors.initials: WH
authors.lastname: Colledge
authors.forename: Heike L
authors.initials: HL
authors.lastname: Pahl
mesh_terms: D000818:Animals; D002460:Cell Line; D003550:Cystic Fibrosis / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D018181:Mice, Inbred CFTR; D016328:NF-kappa B / Q000096:biosynthesis*; D015533:Transcriptional Activation
chemical_list: C505032:CFTR protein, human; D016328:NF-kappa B; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator