CFTR Expression and ER-Associated Degradation in Yeast

The most common cause of cystic fibrosis is the deletion of a phenylalanine at position 508 (gDF508) of the cystic fibrosis transmembrane conductance regulator (CFTR). Although the majority of wild-type CFTR is degraded in the endoplasmic reticulum (ER), suggesting that its folding efficiency is low, almost all of the AF508 variant is destroyed (1 -4 ). The process in which the ER quality control system ensures that misfolded or aberrant proteins, such as AF508 CFTR, are proteolyzed and thus prevented from entering the secretory pathway has been termed ER associated degradation, or ERAD (5). It remains unclear how CFTR, or other ERAD substrates, are first selected and then targeted for destruction, but a group of factors known as molecular chaperones may play a pivotal role in this process, as they associate with CFTR in the ER and are released upon protein maturation or degradation (6 -8 ). In accordance with this hypothesis, molecular chaperones are known to aid in protein targeting to proteosome-like complexes in bacteria (9 ).