Pregnane X receptor (PXR) is a major transcriptional regulator of xenobiotic metabolism and transport pathways in the liver and intestines, which are critical for protecting organisms against potentially harmful xenobiotic and endobiotic compounds. Inadvertent activation of drug metabolism pathways through PXR is known to contribute to drug resistance, adverse drug-drug interactions, and drug toxicity in humans. In both humans and rodents, PXR has been implicated in non-alcoholic fatty liver disease, diabetes, obesity, inflammatory bowel disease, and cancer. Because of PXR's important functions, it has been a therapeutic target of interest for a long time. More recent mechanistic studies have shown that PXR is modulated by multiple PTMs. Herein we provide the first investigation of the role of acetylation in modulating PXR activity. Through LC-MS/MS analysis, we identified lysine 109 (K109) in the hinge as PXR's major acetylation site. Using various biochemical and cell-based assays, we show that PXR's acetylation status and transcriptional activity are modulated by E1A binding protein (p300) and sirtuin 1 (SIRT1). Based on analysis of acetylation site mutants, we found that acetylation at K109 represses PXR transcriptional activity. The mechanism involves loss of RXRα dimerization and reduced binding to cognate DNA response elements. This mechanism may represent a promising therapeutic target using modulators of PXR acetylation levels. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.

• MeSH
• acetylace MeSH
• aktivace transkripce * MeSH
• buňky Hep G2 MeSH
• DNA chemie   metabolismus   MeSH
• Escherichia coli genetika   metabolismus   MeSH
• HEK293 buňky MeSH
• HeLa buňky MeSH
• klonování DNA MeSH
• lidé MeSH
• luciferasy genetika   metabolismus   MeSH
• lysin chemie   metabolismus   MeSH
• molekulární modely MeSH
• multimerizace proteinu MeSH
• mutageneze cílená MeSH
• posttranslační úpravy proteinů * MeSH
• rekombinantní proteiny chemie   genetika   metabolismus   MeSH
• reportérové geny MeSH
• responzivní elementy MeSH
• sekundární struktura proteinů MeSH
• sirtuin 1 genetika   metabolismus   MeSH
• steroidní receptory chemie   genetika   metabolismus   MeSH
• strukturní homologie proteinů MeSH
• transkripční faktory p300-CBP genetika   metabolismus   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH