Freedom of expression. Focus on “Endoplasmic reticulum stress and the unfolded protein response regulate cystic fibrosis transmembrane conductance regulator expression”

2007 ◽  
Vol 292 (2) ◽  
pp. C687-C688 ◽  
Author(s):  
Neil A. Bradbury
Keyword(s):  
Cystic Fibrosis ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Freedom Of Expression ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Cystic Fibrosis Transmembrane

Endoplasmic reticulum stress and the unfolded protein response regulate genomic cystic fibrosis transmembrane conductance regulator expression

2007 ◽  
Vol 292 (2) ◽  
pp. C756-C766 ◽  
Author(s):  
András Rab ◽  
Rafal Bartoszewski ◽  
Asta Jurkuvenaite ◽  
John Wakefield ◽  
James F. Collawn ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Er Stress ◽  
Mrna Levels ◽  
Transmembrane Conductance Regulator ◽  
Wild Type ◽  
Transmembrane Conductance ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Cystic Fibrosis Transmembrane

The unfolded protein response (UPR) is a cellular recovery mechanism activated by endoplasmic reticulum (ER) stress. The UPR is coordinated with the ER-associated degradation (ERAD) to regulate the protein load at the ER. In the present study, we tested how membrane protein biogenesis is regulated through the UPR in epithelia, using the cystic fibrosis transmembrane conductance regulator (CFTR) as a model. Pharmacological methods such as proteasome inhibition and treatment with brefeldin A and tunicamycin were used to induce ER stress and activate the UPR as monitored by increased levels of spliced XBP1 and BiP mRNA. The results indicate that activation of the UPR is followed by a significant decrease in genomic CFTR mRNA levels without significant changes in the mRNA levels of another membrane protein, the transferrin receptor. We also tested whether overexpression of a wild-type CFTR transgene in epithelia expressing endogenous wild-type CFTR activated the UPR. Although CFTR maturation is inefficient in this setting, the UPR was not activated. However, pharmacological induction of ER stress in these cells also led to decreased endogenous CFTR mRNA levels without affecting recombinant CFTR message levels. These results demonstrate that under ER stress conditions, endogenous CFTR biogenesis is regulated by the UPR through alterations in mRNA levels and posttranslationally by ERAD, whereas recombinant CFTR expression is regulated only by ERAD.

scholarly journals An essential dimer-forming subregion of the endoplasmic reticulum stress sensor Ire1

2005 ◽  
Vol 391 (1) ◽  
pp. 135-142 ◽  
Author(s):  
Daisuke Oikawa ◽  
Yukio Kimata ◽  
Masato Takeuchi ◽  
Kenji Kohno
Keyword(s):  
Endoplasmic Reticulum ◽  
Recombinant Protein ◽  
Endoplasmic Reticulum Stress ◽  
Transmembrane Protein ◽  
Type I ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Recombinant Fragments ◽  
Made In

The luminal domain of the type I transmembrane protein Ire1 senses endoplasmic reticulum stress by an undefined mechanism to up-regulate the signalling pathway for the unfolded protein response. Previously, we proposed that the luminal domain of yeast Ire1 is divided into five subregions, termed subregions I–V sequentially from the N-terminus. Ire1 lost activity when internal deletions of subregion II or IV were made. In the present paper, we show that partial proteolysis of a recombinant protein consisting of the Ire1 luminal domain suggests that subregions II–IV are tightly folded. We also show that a recombinant protein of subregions II–IV formed homodimers, and that this homodimer formation was impaired by an internal deletion of subregion IV. Furthermore, recombinant fragments of subregion IV exhibited a self-binding ability. Therefore, although its sequence is little conserved evolutionarily, subregion IV plays an essential role to promote Ire1 dimer formation.

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