Polycystic Liver Disease and ER Quality Control

描述(申请人提供)：常染色体显性遗传性多囊肝病(PCLD)基因的产物影响膜蛋白和分泌蛋白的折叠和质量控制。PCLD基因PRKCSH和SEC63编码内质网蛋白Sec63和葡萄糖苷酶II b，内质网蛋白Sec63是腔内ER伴侣Bip的辅助因子，葡萄糖苷酶II b调节糖蛋白与凝集素伴侣Calnexin和Calreticrin的相互作用。这些突变如何促进肝胆管细胞(胆管细胞)的囊性形成，同时在大多数其他组织中保持有效沉默，目前尚不清楚。为了分析PCLD的分子机制，我们将建立PCLD的组织培养模型，并研究PCLD突变的细胞后果。具体地说，我们将1)建立和鉴定PCLD胆管细胞系，以及2)使用PCLD细胞系来确定PCLD突变体的下游靶点。这些研究将提供一些对PCLD细胞生物学的初步见解，并将确定需要Sec63和葡萄糖苷酶IIb活性的底物。

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.