Dioxin receptor is a ligand-dependent E3 ubiquitin ligase
Dioxin receptor is a ligand-dependent E3 ubiquitin ligase
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DOI：
10.1038/nature05683
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发表时间：
2007-03-29
期刊：
影响因子：
64.8
通讯作者：
Kato, Shigeaki
中科院分区：
文献类型：
--
作者：
Ohtake, Fumiaki;Baba, Atsushi;Kato, Shigeaki
脂溶性配体，包括性类固醇激素和环境毒素，激活配体依赖的dna序列特异性转录因子，通过靶基因选择性转录调控转导信号(1)。然而，脂溶性配体信号通过其他靶标选择系统的细胞感知机制尚不清楚。泛素-蛋白酶体系统调节选择性蛋白质降解，其中E3泛素连接酶决定靶特异性（2-4）。在这里，我们描述了人类细胞系中脂溶性配体依赖的泛素连接酶复合物，其中二英受体（AhR）（5-9）被整合为一种新型cullin 4B泛素连接酶复合物CUL4B（AhR）的组成部分。体外和体内CUL4B（AhR）的复合物组装和泛素连接酶活性依赖于AhR配体。在CUL4B（AhR）复合体中，配体激活的AhR作为一种底物特异性接头成分，靶向性类固醇受体进行降解。因此，我们的研究结果揭示了AhR作为泛素连接酶复合物的非典型组分的功能，并证明了脂溶性配体通过泛素连接酶复合物调节靶蛋白选择性降解的非基因组信号通路。
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 regulation(1). 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(2-4). Here we characterize a fat-soluble ligand-dependent ubiquitin ligase complex in human cell lines, in which dioxin receptor ( AhR)(5-9) 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.