The most common Cystic Fibrosis-causing mutation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), F508del-CFTR, has abnormal biogenesis. F508del-CFTR does not appropriately exit the endoplasmic reticulum (ER), and therefore, does not traffic through the Golgi and reach its appropriate functional location at the apical plasma membrane of epithelial cells. Similar defects in biogenesis and trafficking of nascent proteins underly other inherited diseases, including Alpha-1 Antitrypsin Deficiency and rare forms of inherited diabetes.
The Rubenstein lab has focused on the mechanisms by which a prototype small molecule, 4-phenylbutyrate (4PBA), can correct the abnormal biogenesis of F508del-CFTR. Through this work, we identified that 4PBA increased the expression of ERp29, a novel molecular chaperone of the ER lumen, that ERp29 is required for normal biogenesis of wild type CFTR, and that ERp29 can correct F508del-CFTR trafficking when over-expressed. Building on these discoveries, our group’s studies presently focus on several questions regarding ERp29, including:
- What are the functional features of ERp29 that allow it to promote proper biogenesis of its client proteins through the Golgi?
- How does interaction of a client with ERp29 in the lumen of the ER promote interaction of client with trafficking machinery that is primarily in the cytoplasm?
- Do mutations in client proteins, such as CFTR, that prevent interaction with ERp29 in turn prevent normal client biogenesis?
- Is there an alternate pathway by which clients exit the ER if they do not interact with ERp29?
These studies presently utilize cellular model systems, and we are developing new model systems to address these questions through new collaborations.