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J Biol Chem. 2016 Nov 25;291(48):25120-25132. Epub 2016 Oct 4.

Ohgata, the Single Drosophila Ortholog of Human Cereblon, Regulates Insulin Signaling-dependent Organismic Growth.

Author information

1
From the Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan.
2
From the Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan, naoya.sawamura@gmail.com.
3
the Research Organization for Nano-life Innovation, Waseda University, Shinjuku, Tokyo 162-0041, Japan.
4
the Faculty of Biology, Medicine and Health, The University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom.
5
the German Center for Neurodegenerative Diseases (DZNE), c/o Life and Medical Sciences (LIMES) Institute, Carl-Troll-Strasse 31, 53115 Bonn, Germany, and.
6
From the Faculty of Science and Engineering, Waseda University, TWIns, 2-2 Wakamatsu, Shinjuku, Tokyo 162-8480, Japan, tasahi@waseda.jp.
7
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.

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.

KEYWORDS:

CRISPR/Cas; Cereblon; Drosophila genetics; E3 ubiquitin ligase; development; insulin

PMID:
27702999
PMCID:
PMC5122779
DOI:
10.1074/jbc.M116.757823
[Indexed for MEDLINE]
Free PMC Article

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