Fat-soluble ligands, including sex steroid hormones and environmental toxins, activate ligand-dependent DNA-sequence-specific transcriptional factors that transduce signals through target-gene-selective transcriptional regulation1. However, the mechanisms of cellular perception of fat-soluble ligand signals through other target-selective systems remain unclear. The ubiquitin–proteasome system regulates selective protein degradation, in which the E3 ubiquitin ligases determine target specificity2,3,4. Here we characterize a fat-soluble ligand-dependent ubiquitin ligase complex in human cell lines, in which dioxin receptor (AhR)5,6,7,8,9 is integrated as a component of a novel cullin 4B ubiquitin ligase complex, CUL4BAhR. Complex assembly and ubiquitin ligase activity of CUL4BAhR in vitro and in vivo are dependent on the AhR ligand. In the CUL4BAhR complex, ligand-activated AhR acts as a substrate-specific adaptor component that targets sex steroid receptors for degradation. Thus, our findings uncover a function for AhR as an atypical component of the ubiquitin ligase complex and demonstrate a non-genomic signalling pathway in which fat-soluble ligands regulate target-protein-selective degradation through a ubiquitin ligase complex.
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We thank K. Tanaka, C. K. Glass, J. Yanagisawa, Y. Gotoh and J. Mimura for comments; S. Murata, T. Matsuda, T. Suzuki and Y. Tateishi for providing materials; T. Matsumoto, M. Igarashi and S. Fujiyama for technical assistance; and H. Higuchi for manuscript preparation. This work was supported in part by the Program for Promotion of Basic Research Activities for Innovative Biosciences (PROBRAIN) and priority areas from the Ministry of Education, Culture, Sports, Science and Technology (to Y.F.-K. and S.K.).
Author Contributions F.O., T.C., Y.F.-K. and S.K. designed the experiments. F.O., A B., M.O., K I., H.M., S.T. and I. T. performed the experiments. F.O., A.K. and S.K. wrote the paper.
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
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Ohtake, F., Baba, A., Takada, I. et al. Dioxin receptor is a ligand-dependent E3 ubiquitin ligase. Nature 446, 562–566 (2007). https://doi.org/10.1038/nature05683
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