Coupling cystic fibrosis to endoplasmic reticulum stress: Differential role of Grp78 and ATF6

Biochim Biophys Acta. 2007 Dec;1772(11-12):1236-49. doi: 10.1016/j.bbadis.2007.10.004. Epub 2007 Nov 4.


Cystic fibrosis (CF) is the most common Caucasian autosomal recessive disease. It is due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding the CFTR protein, which is a chloride (Cl(-)) channel. The most common mutation leads to a missing phenylalanine at position 508 (DeltaF508). The DeltaF508-CFTR protein is misfolded and retained in the endoplasmic reticulum and may trigger the unfolded protein response (UPR). Furthermore, CF is accompanied by inflammation and infection, which are also involved in the UPR. To date, the UPR transducer ATF6 and ER stress sensor Grp78 have been used as UPR markers. Therefore, our aim was to study the activation of ATF6 and Grp78 in transfected human epithelial cells expressing the DeltaF508-CFTR protein, and we showed that they are activated in these cells. We investigated the effect of exogenous UPR inducers thapsigargin (Tg) and tunicamycin (Tu) on Grp78 and ATF6 expression. Whereas the cells reacted to the UPR induction, we show a difference in the electrophoretic pattern of ATF6. The Grp78/ATF6 complex was previously described, but its stability during UPR is controversial. Using co-immunoprecipitation we show that it is stable in DeltaF508-CFTR-expressing cells and is maintained under UPR conditions. Finally, using siRNA, we show that decreased ATF6 expression induces increased cAMP-dependent halide flux through DeltaF508-CFTR due to its increased membrane localization. Therefore, our results suggest that UPR may be triggered in CF and that ATF6 may be a therapeutic target.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 6 / metabolism*
  • Cell Line
  • Cell Membrane / drug effects
  • Cyclic AMP / metabolism
  • Cystic Fibrosis / metabolism*
  • Cystic Fibrosis / pathology*
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / pathology*
  • Endoplasmic Reticulum Chaperone BiP
  • Genetic Vectors
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Molecular Chaperones / metabolism*
  • Protein Binding / drug effects
  • Protein Folding
  • Protein Isoforms / metabolism
  • Protein Transport / drug effects
  • RNA, Small Interfering / metabolism
  • Thapsigargin / pharmacology
  • Transfection
  • Tunicamycin / pharmacology


  • Activating Transcription Factor 6
  • Endoplasmic Reticulum Chaperone BiP
  • HSPA5 protein, human
  • Heat-Shock Proteins
  • Molecular Chaperones
  • Protein Isoforms
  • RNA, Small Interfering
  • cystic fibrosis transmembrane conductance regulator delta F508
  • Tunicamycin
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Thapsigargin
  • Cyclic AMP