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Liver X Receptor Ligands Suppress Ubiquitination and Degradation of LXR by Displacing BARD1/BRCA1

School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Sillim-Dong, Kwanak-Gu, Seoul 151-742, Korea

Address all correspondence and requests for reprints to: Jae Bum Kim, School of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, San 56-1, Sillim-Dong, Kwanak-Gu, Seoul 151-742, Korea. E-mail: jaebkim{at}snu.ac.kr.

Liver X receptor (LXR) is a ligand-activated transcription factor that plays important roles in cholesterol and lipid homeostasis. However, ligand-induced posttranslational modification of LXR is largely unknown. Here, we show that ligand-free LXR is rapidly degraded by ubiquitination. Without ligand, LXR interacts with an ubiquitin E3-ligase protein complex containing breast and ovarian cancer susceptibility 1 (BRCA1)-associated RING domain 1 (BARD1). Interestingly, LXR ligand represses ubiquitination and degradation of LXR, and the interaction between LXR and BARD1 is inhibited by LXR ligand. Consistently, T0901317, a synthetic LXR ligand, increased the level of LXR protein in liver. Moreover, overexpression of BARD1/BRCA1 promoted the ubiquitination of LXR and reduced the recruitment of LXR to the target gene promoters, whereas BARD1 knockdown reversed such effects. Taken together, these data suggest that LXR ligand prevents LXR from ubiquitination and degradation by detaching BARD1/BRCA1, which might be critical for the early step of transcriptional activation of ligand-stimulated LXR through a stable binding of LXR to the promoters of target genes.

NURSA Molecule Pages Link:

Nuclear Receptors:   LXRα

Ligands:   22α-Hydroxycholesterol  |  T0901317  |  GW 3965