title: The E3 ubiquitin ligase gp78 protects against ER stress in zebrafish liver.
abstract: Enhanced endoplasmic reticulum (ER)-associated protein degradation (ERAD) activity by the unfolded protein response (UPR) represents one of the mechanisms for restoring ER homeostasis. In vitro evidence indicates that the mammalian gp78 protein is an E3 ubiquitin ligase that facilitates ERAD by polyubiquitinating and targeting proteins for proteasomal degradation under both physiologic and stress conditions. However, the in vivo function of gp78 in maintaining ER protein homeostasis remains untested. Here we show that like its mammalian counterpart, the zebrafish gp78 is also an E3 ubiquitin ligase as revealed by in vitro ubiquitination assays. Expression analysis uncovered that gp78 is highly expressed in several organs, including liver and brain, of both larval and adult fish. Treatment of larvae or adult fish with tunicamycin induces ER stress and upregulates the expression of several key components of the gp78 ERAD complex in the liver. Moreover, liver-specific overexpression of the dominant-negative form of gp78 (gp78-R2M) renders liver more sensitive to tunicamycin-induced ER stress and enhances the expression of sterol response element binding protein (Srebp)-target genes, which was largely suppressed in fish overexpressing wild-type gp78. Together, these data indicate that gp78 plays a critical role in protecting against ER stress in liver.
authors: Center for Biomedical Engineering and Technology, Baltimore, MD 21202, USA; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors: Zhiliang
authors: Z
authors: Chen
authors: Faculty of Pharmacy, Biochemistry Department, Ege University, Izmir 35100, Turkey.
authors: Petek
authors: P
authors: Ballar
authors: Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China.
authors: Yu
authors: Y
authors: Fu
authors: Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
authors: Jia
authors: J
authors: Luo
authors: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21202, USA. Electronic address: sdu@som.umaryland.edu.
authors: Shaojun
authors: S
authors: Du
authors: Center for Biomedical Engineering and Technology, Baltimore, MD 21202, USA; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Electronic address: sfang@umaryland.edu.
authors: Shengyun
authors: S
authors: Fang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007814:Larva / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000196:embryology* / Q000201:enzymology* / Q000378:metabolism; D008969:Molecular Sequence Data; D021381:Protein Transport / Q000187:drug effects; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics; D014415:Tunicamycin / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D015027:Zebrafish / Q000196:embryology*
chemical_list: D051779:Sterol Regulatory Element Binding Proteins; D014415:Tunicamycin; D044767:Ubiquitin-Protein Ligases
keywords: Cholesterol; ERAD; Lipogenesis; UPR; Zebrafish; gp78/AMFR