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.

Department of Cell Biology and Genetics Faculty of Science Palacky University Olomouc Slechtitelu Olomouc Czech Republic

Department of Chemistry University of North Carolina Chapel Hill NC 27599 USA

Department of Genetics Albert Einstein College of Medicine Bronx NY 10461 USA

Department of Genetics Albert Einstein College of Medicine Bronx NY 10461 USA; Department of Medicine Albert Einstein College of Medicine Bronx NY 10461 USA

Department of Microbiology and Immunology Drexel University College of Medicine Philadelphia PA 19129 USA

Department of Microbiology Raidighi College West Bengal India

Department of Pathology University of Iowa Hospitals and Clinics Iowa City IA 52242 USA

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