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.

The E3 ubiquitin ligase component, Cereblon, is an evolutionarily conserved regulator of Wnt signaling

“…7a, di–iii ). We performed RNAi-mediated knockdown of the CRBN ortholog, ohgata ( ohgt ) 45 , in the posterior compartment of the wing imaginal disc and observed significantly disrupted Sens expression across the posterior region of wing disks (Fig. 7biv–vi, c and Supplementary Fig.…”

The Neuroprotective Effect of Thalidomide against Ischemia through the Cereblon-mediated Repression of AMPK Activity

“…CRBN -deficient mice showed the activation of AMPK and resistance to high-fat diet-induced obesity and insulin resistance 33 . We also identified that Ohgata (OHGT), the Drosophila ortholog of CRBN as a novel regulator of insulin-dependent organismic growth in Drosophila 34 . It has a possibility that CRBN directly regulates insulin-dependent signaling pathway in the molecular mechanism of thalidomide’s neuroprotective effect on cerebral infarction.…”

droTAG: Adapting dTAG Toolkit to Drosophila Melanogaster

“…In contrast, here we would like to focus the attention on the conservation of all components of the mammalian CRL4 complex in Drosophila, including the Cullin 4 homolog and the DDB1 homolog PIC [8]. In particular, it must be emphasized that there is a 44% of aminoacidic identity in thalidomide binding domain (TBD) between human CRBN and Drosophila OHGT (Figure 1A) [9]. This data strongly supports the idea that the function of the ubiquitin ligase complex is evolutionary conserved in Drosophila melanogaster, making the hypothetical applicability of dTAG in Drosophila (droTAG), a powerful strategy that is worth to be developed (Figure 1B).…”