1. ERATO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
2. Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
3. Department of Urology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-8655, Japan
4. National Institute for Environmental Studies, Tsukuba, Ibaraki 305-8506, Japan
5. Graduate School of Life and Environmental Sciences, and,
6. TARA Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8577, Japan
7. SORST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan

Correspondence to: Shigeaki Kato^1,2 Correspondence and requests for materials should be addressed to S.K. (Email: uskato@mail.ecc.u-tokyo.ac.jp).

Abstract

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 specificity^{2, 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, CUL4B^AhR. Complex assembly and ubiquitin ligase activity of CUL4B^AhR in vitro and in vivo are dependent on the AhR ligand. In the CUL4B^AhR 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.

1. ERATO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
2. Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan
3. Department of Urology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-8655, Japan
4. National Institute for Environmental Studies, Tsukuba, Ibaraki 305-8506, Japan
5. Graduate School of Life and Environmental Sciences, and,
6. TARA Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, 305-8577, Japan
7. SORST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan

Correspondence to: Shigeaki Kato^1,2 Correspondence and requests for materials should be addressed to S.K. (Email: uskato@mail.ecc.u-tokyo.ac.jp).

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