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1 Cell Biology, UAB, Birmingham, Alabama, United States
2 Tranzyme Inc, Birmingham, Alabama, United States
* To whom correspondence should be addressed. E-mail: bebok{at}uab.edu.
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, 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 over-expression of a wild type CFTR transgene in epithelia expressing endogenous wild type CFTR activates the UPR. While CFTR maturation is inefficient in this setting, the UPR was not activated. However, pharmacological induction of ER stress in these cells also leads 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 post-translationally by ERAD, while recombinant CFTR expression is regulated only by ERAD.
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