title: Acetylation of lysine 109 modulates pregnane X receptor DNA binding and transcriptional activity.
abstract: 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.
authors: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Danielle
authors: D
authors: Pasquel
authors: Department of Cell Biology and Genetics, Faculty of Science, Palacky University Olomouc, Slechtitelu, Olomouc, Czech Republic.
authors: Aneta
authors: A
authors: Doricakova
authors: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Hao
authors: H
authors: Li
authors: Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
authors: Sandhya
authors: S
authors: Kortagere
authors: Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA.
authors: Matthew D
authors: MD
authors: Krasowski
authors: Department of Microbiology, Raidighi College, West Bengal, India.
authors: Arunima
authors: A
authors: Biswas
authors: Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: William G
authors: WG
authors: Walton
authors: Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA.
authors: Matthew R
authors: MR
authors: Redinbo
authors: Department of Cell Biology and Genetics, Faculty of Science, Palacky University Olomouc, Slechtitelu, Olomouc, Czech Republic. Electronic address: moulin@email.cz.
authors: Zdenek
authors: Z
authors: Dvorak
authors: Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: sridhar.mani@einstein.yu.edu.
authors: Sridhar
authors: S
authors: Mani
mesh_terms: D000107:Acetylation; D003001:Cloning, Molecular; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D017930:Genes, Reporter; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D000077297:Pregnane X Receptor; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D017433:Protein Structure, Secondary; D011987:Receptors, Steroid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D004247:DNA; D008156:Luciferases; D008239:Lysine; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D011994:Recombinant Proteins; D056564:Sirtuin 1; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C447939:SIRT1 protein, human
keywords: Acetylation; Drug metabolism; E1A binding protein p300 (p300); Nuclear receptor; Post-translational modification (PTM); Pregnane X receptor (PXR); Transcription regulation