Liver X receptor ligands suppress ubiquitination and degradation of LXRalpha by displacing BARD1/BRCA1.
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 LXRalpha is rapidly degraded by ubiquitination. Without ligand, LXRalpha 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 LXRalpha, and the interaction between LXRalpha and BARD1 is inhibited by LXR ligand. Consistently, T0901317, a synthetic LXR ligand, increased the level of LXRalpha protein in liver. Moreover, overexpression of BARD1/BRCA1 promoted the ubiquitination of LXRalpha and reduced the recruitment of LXRalpha to the target gene promoters, whereas BARD1 knockdown reversed such effects. Taken together, these data suggest that LXR ligand prevents LXRalpha from ubiquitination and degradation by detaching BARD1/BRCA1, which might be critical for the early step of transcriptional activation of ligand-stimulated LXRalpha through a stable binding of LXRalpha to the promoters of target genes.
Kim
Kang Ho
KH
Institute of Molecular Biology and Genetics, Seoul National University, Kwanak-Gu, Seoul 151-742, Korea.
Yoon
Jeong Min
JM
Choi
A Hyun
AH
Kim
Woo Sik
WS
Lee
Gha Young
GY
Kim
Jae Bum
JB
D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D000071518:Liver X Receptors; D009154:Mutation; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D025521:Tumor Suppressor Proteins; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases