Am J Physiol Cell Physiol AJP: Lung Cellular and Molecular Physiology
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Am J Physiol Cell Physiol 292: C756-C766, 2007. First published September 20, 2006; doi:10.1152/ajpcell.00391.2006 Free Article
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PROTEIN AND VESICLE TRAFFICKING, CYTOSKELETON

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

András Rab,1,2 Rafal Bartoszewski,1 Asta Jurkuvenaite,1 John Wakefield,3 James F. Collawn,1,2 and Zsuzsa Bebok1,2

1Department of Cell Biology and 2The Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham; and 3Tranzyme Corporation, Birmingham, Alabama

Submitted 14 July 2006 ; accepted in final form 16 September 2006

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.

endoplasmic reticulum-associated degradation; messenger ribonucleic acid


Address for reprint requests and other correspondence: Z. Bebok, Dept. of Cell Biology, Univ. of Alabama at Birmingham, 1918 Univ. Blvd., MCLM 760, Birmingham, AL 35294-0005 (e-mail: bebok{at}uab.edu)


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