title: Molecular characterization of hepatocystin, the protein that is defective in autosomal dominant polycystic liver disease.
abstract: OBJECTIVE
  Autosomal dominant polycystic liver disease is characterized by the presence of numerous cysts spread throughout the liver parenchyma. Recently, we discovered that polycystic liver disease is caused by mutations in the protein kinase C substrate 80K-H gene, which encodes a protein named hepatocystin. Previous studies have identified hepatocystin as a protein kinase C substrate, a component of a cytosolic signal transduction complex, a receptor for advanced glycation end products, a vacuolar protein, and the beta subunit of endoplasmic reticulum glucosidase II. Thus, the exact localization and cellular function of hepatocystin remain unclear.
  
  
  METHODS
  The localization and biochemical properties of normal and polycystic liver disease mutant forms of hepatocystin were examined by using a combination of immunofluorescence microscopy, immunoblotting, metabolic labeling, immunoprecipitation, and carbohydrate analyses.
  
  
  RESULTS
  Normal hepatocystin localizes to the endoplasmic reticulum, where it assembles with the glucosidase II alpha subunit. The 1338-2A-->G truncating mutation in hepatocystin observed in some polycystic liver disease patients produces a protein that is not retained in the endoplasmic reticulum but is secreted into the medium. This mutant protein fails to assemble with the glucosidase II alpha subunit. As a consequence, mutant hepatocystin is undetectable in liver cysts. In addition, levels of normal hepatocystin and of the glucosidase II alpha subunit are substantially reduced in liver and Epstein-Barr virus-immortalized B lymphoblasts from patients with polycystic liver disease.
  
  
  CONCLUSIONS
  These findings are consistent with a role of hepatocystin in carbohydrate processing and quality control of newly synthesized glycoproteins in the endoplasmic reticulum. Therefore, altered endoplasmic reticulum processing of some key regulator of cell proliferation may underlie polycystic liver disease.
authors.affiliation: Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 18T, Room 101, Bethesda, MD 20892, USA. joostphdrenth@cs.com
authors.forename: Joost P H
authors.initials: JP
authors.lastname: Drenth
authors.forename: Jose A
authors.initials: JA
authors.lastname: Martina
authors.forename: Rene H M
authors.initials: RH
authors.lastname: Te Morsche
authors.forename: Jan B M J
authors.initials: JB
authors.lastname: Jansen
authors.forename: Juan S
authors.initials: JS
authors.lastname: Bonifacino
mesh_terms: D002135:Calcium-Binding Proteins; D002455:Cell Division; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015870:Gene Expression; D005799:Genes, Dominant; D005959:Glucosidases; D006031:Glycosylation; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008107:Liver Diseases / Q000235:genetics* / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology; D008565:Membrane Proteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism*; D000520:alpha-Glucosidases / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; C034251:4-nitrophenyl-alpha-glucosidase; D005959:Glucosidases; C070368:PRKCSH protein, human; D000520:alpha-Glucosidases