Polycystic Liver Disease and ER Quality Control

DESCRIPTION (provided by applicant): The products of the autosomal-dominant polycystic liver disease (PCLD) genes affect the folding and quality control of membrane and secretory proteins. The PCLD genes, PRKCSH and SEC63, encode the endoplasmic reticulum (ER) proteins Sec63, a cofactor for the lumenal ER chaperone BiP, and glucosidase II b, which modulates glycoprotein interactions with the lectin chaperones calnexin and calreticulin. How these mutations promote cyst formation in hepatic biliary duct cells (cholangiocytes) while remaining effectively silent in most other tissues remains unclear. To dissect the molecular mechanisms of PCLD, we will develop a tissue culture model for PCLD and will investigate the cellular consequences of the PCLD mutations. Specifically, we will 1) Establish and characterize PCLD cholangiocyte cell lines, and 2) Use the PCLD cell lines to identify downstream targets of the PCLD mutants. These studies will provide some of the first insights into the cell biology of PCLD and will identify substrates that require the activities of Sec63 and glucosidase IIb.