title: Hepatocystin is Essential for TRPM7 Function During Early Embryogenesis.
abstract: Mutations in protein kinase C substrate 80K-H (PRKCSH), which encodes for an 80 KDa protein named hepatocystin (80K-H, PRKCSH), gives rise to polycystic liver disease (PCLD). Hepatocystin functions as the noncatalytic beta subunit of Glucosidase II, an endoplasmic reticulum (ER)-resident enzyme involved in processing and quality control of newly synthesized glycoproteins. Patients harboring heterozygous germline mutations in PRKCSH are thought to develop renal cysts as a result of somatic loss of the second allele, which subsequently interferes with expression of the TRP channel polycystin-2 (PKD2). Deletion of both alleles of PRKCSH in mice results in embryonic lethality before embryonic day E11.5. Here, we investigated the function of hepatocystin during Xenopus laevis embryogenesis and identified hepatocystin as a binding partner of the TRPM7 ion channel, whose function is required for vertebrate gastrulation. We find that TRPM7 functions synergistically with hepatocystin. Although other N-glycosylated proteins are critical to early development, overexpression of TRPM7 in Xenopus laevis embryos was sufficient to fully rescue the gastrulation defect caused by loss of hepatocystin. We observed that depletion of hepatocystin in Xenopus laevis embryos decreased TRPM7 expression, indicating that the early embryonic lethality caused by loss of hepatocystin is mainly due to impairment of TRPM7 protein expression.
authors.affiliation: Rutgers-Robert Wood Johnson Medical School, Dept. of Pharmacology, Piscataway, 08854, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Overton
authors.affiliation: Rutgers-Robert Wood Johnson Medical School, Dept. of Pharmacology, Piscataway, 08854, USA.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Komiya
authors.affiliation: Temple University, Dept. of Biology, Philadelphia, 19122, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Mezzacappa
authors.affiliation: Temple University, Dept. of Biology, Philadelphia, 19122, USA.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Nama
authors.affiliation: Rutgers-Robert Wood Johnson Medical School, Dept. of Pharmacology, Piscataway, 08854, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Cai
authors.affiliation: Rutgers-Robert Wood Johnson Medical School, Dept. of Pharmacology, Piscataway, 08854, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Lou
authors.affiliation: Yale University School of Medicine, Dept. of Internal Medicine, New Haven, 06510, USA.
authors.forename: Sorin V
authors.initials: SV
authors.lastname: Fedeles
authors.affiliation: Temple University, Dept. of Biology, Philadelphia, 19122, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Habas
authors.affiliation: Rutgers-Robert Wood Johnson Medical School, Dept. of Pharmacology, Piscataway, 08854, USA.
authors.forename: Loren W
authors.initials: LW
authors.lastname: Runnels
mesh_terms: D000818:Animals; D002460:Cell Line; D004625:Embryo, Nonmammalian / Q000196:embryology*; D047108:Embryonic Development / Q000502:physiology*; D005775:Gastrula / Q000196:embryology*; D005959:Glucosidases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D050053:TRPM Cation Channels; C556687:TRPM7 protein, Xenopus; D029867:Xenopus Proteins; D005959:Glucosidases