DeltaF508-CFTR causes constitutive NF-kappaB activation through an ER-overload response in cystic fibrosis lungs

Biol Chem. 2002 Feb;383(2):271-82. doi: 10.1515/BC.2002.029.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cystic Fibrosis / complications
  • Cystic Fibrosis / genetics*
  • Cystic Fibrosis / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Disease Models, Animal
  • Endoplasmic Reticulum / metabolism*
  • Humans
  • Lung / metabolism*
  • Lung / ultrastructure
  • Mice
  • Mice, Inbred CFTR
  • NF-kappa B / biosynthesis*
  • Transcriptional Activation

Substances

  • CFTR protein, human
  • NF-kappa B
  • cystic fibrosis transmembrane conductance regulator delta F508
  • Cystic Fibrosis Transmembrane Conductance Regulator