Dioxin receptor is a ligand-dependent E3 ubiquitin ligase.
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. 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. Here we characterize a fat-soluble ligand-dependent ubiquitin ligase complex in human cell lines, in which dioxin receptor (AhR) 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.
Ohtake
Fumiaki
F
ERATO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
Baba
Atsushi
A
Takada
Ichiro
I
Okada
Maiko
M
Iwasaki
Kei
K
Miki
Hiromi
H
Takahashi
Sayuri
S
Kouzmenko
Alexander
A
Nohara
Keiko
K
Chiba
Tomoki
T
Fujii-Kuriyama
Yoshiaki
Y
Kato
Shigeaki
S
D002460:Cell Line; D044842:Cullin Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D006801:Humans; D008024:Ligands; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D015533:Transcriptional Activation
C517832:CUL4B protein, human; D044842:Cullin Proteins; D047628:Estrogen Receptor alpha; D008024:Ligands; D046912:Multiprotein Complexes; D018336:Receptors, Aryl Hydrocarbon