DeltaF508-CFTR causes constitutive NF-kappaB activation through an ER-overload response in cystic fibrosis lungs.
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.
Knorre
Alexander
A
Department of Experimental Anaesthesiology, University Hospital Freiburg, Germany.
Wagner
Mathias
M
Schaefer
Hans-Eckart
HE
Colledge
William H
WH
Pahl
Heike L
HL
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
C505032:CFTR protein, human; D016328:NF-kappa B; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator