title: Ohgata, the Single Drosophila Ortholog of Human Cereblon, Regulates Insulin Signaling-dependent Organismic Growth.
abstract: Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that is highly conserved in animals and plants. CRBN proteins have been implicated in various biological processes such as development, metabolism, learning, and memory formation, and their impairment has been linked to autosomal recessive non-syndromic intellectual disability and cancer. Furthermore, human CRBN was identified as the primary target of thalidomide teratogenicity. Data on functional analysis of CRBN family members in vivo, however, are still scarce. Here we identify Ohgata (OHGT), the Drosophila ortholog of CRBN, as a regulator of insulin signaling-mediated growth. Using ohgt mutants that we generated by targeted mutagenesis, we show that its loss results in increased body weight and organ size without changes of the body proportions. We demonstrate that ohgt knockdown in the fat body, an organ analogous to mammalian liver and adipose tissue, phenocopies the growth phenotypes. We further show that overgrowth is due to an elevation of insulin signaling in ohgt mutants and to the down-regulation of inhibitory cofactors of circulating Drosophila insulin-like peptides (DILPs), named acid-labile subunit and imaginal morphogenesis protein-late 2. The two inhibitory proteins were previously shown to be components of a heterotrimeric complex with growth-promoting DILP2 and DILP5. Our study reveals OHGT as a novel regulator of insulin-dependent organismic growth in Drosophila.
authors.affiliation: From the Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Wakabayashi
authors.affiliation: From the Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan, naoya.sawamura@gmail.com.|the Research Organization for Nano-life Innovation, Waseda University, Shinjuku, Tokyo 162-0041, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Sawamura
authors.affiliation: the Faculty of Biology, Medicine and Health, The University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom.
authors.forename: André
authors.identifier: http://orcid.org/0000-0002-7682-5637
authors.initials: A
authors.lastname: Voelzmann
authors.affiliation: the German Center for Neurodegenerative Diseases (DZNE), c/o Life and Medical Sciences (LIMES) Institute, Carl-Troll-Strasse 31, 53115 Bonn, Germany, and.
authors.forename: Meike
authors.initials: M
authors.lastname: Broemer
authors.affiliation: From the Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan, tasahi@waseda.jp.|the Research Organization for Nano-life Innovation, Waseda University, Shinjuku, Tokyo 162-0041, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Asahi
authors.affiliation: Program Unit Development, Genetics and Molecular Physiology, Laboratory for Molecular Developmental Biology, LIMES Institute, University of Bonn, Carl-Troll-Strasse 31, 53115 Bonn, Germany m.hoch@uni-bonn.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoch
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002460:Cell Line; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D055785:Gene Knockdown Techniques; D006801:Humans; D061385:Insulins / Q000235:genetics / Q000378:metabolism; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502543:CRBN protein, human; D029721:Drosophila Proteins; C570846:Ilp5 protein, Drosophila; D061385:Insulins; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases
keywords: CRISPR/Cas; Cereblon; Drosophila genetics; E3 ubiquitin ligase; development; insulin