TY  - JOUR
AU  - Wakabayashi, Satoru
AU  - Sawamura, Naoya
AU  - Voelzmann, André
AU  - Brömer, Meike
AU  - Asahi, Toru
AU  - Hoch, Michael
TI  - Ohgata, the Single Drosophila Ortholog of Human Cereblon, Regulates Insulin Signaling-dependent Organismic Growth.
JO  - The journal of biological chemistry
VL  - 291
IS  - 48
SN  - 0021-9258
CY  - Bethesda, Md.
PB  - Soc.60645
M1  - DZNE-2020-05222
SP  - 25120-25132
PY  - 2016
AB  - 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.
KW  - Adaptor Proteins, Signal Transducing
KW  - Animals
KW  - Cell Line
KW  - Drosophila Proteins: genetics
KW  - Drosophila Proteins: metabolism
KW  - Drosophila melanogaster
KW  - Gene Knockdown Techniques
KW  - Humans
KW  - Insulins: genetics
KW  - Insulins: metabolism
KW  - Peptide Hydrolases: genetics
KW  - Peptide Hydrolases: metabolism
KW  - Signal Transduction: physiology
KW  - Ubiquitin-Protein Ligases
KW  - CRBN protein, human (NLM Chemicals)
KW  - Drosophila Proteins (NLM Chemicals)
KW  - Ilp5 protein, Drosophila (NLM Chemicals)
KW  - Insulins (NLM Chemicals)
KW  - Peptide Hydrolases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:27702999
C2  - pmc:PMC5122779
DO  - DOI:10.1074/jbc.M116.757823
UR  - https://pub.dzne.de/record/138900
ER  -