Acetylation of lysine 109 modulates pregnane X receptor DNA binding and transcriptional activity

Danielle Pasquel, Aneta Doricakova, Hao Li, Sandhya Kortagere, Matthew D. Krasowski, Arunima Biswas, William G. Walton, Matthew R. Redinbo, Zdenek Dvorak, Sridhar Mani

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
JournalBiochimica et Biophysica Acta - Gene Regulatory Mechanisms
DOIs
StateAccepted/In press - Nov 18 2015

Fingerprint

Acetylation
Lysine
DNA
Xenobiotics
Metabolism
Pharmaceutical Preparations
Liver
Sirtuin 1
Drug interactions
Pulse time modulation
Dimerization
Response Elements
Hinges
Medical problems
pregnane X receptor
Drug-Related Side Effects and Adverse Reactions
Drug Interactions
Inflammatory Bowel Diseases
Drug Resistance
Modulators

Keywords

  • Acetylation
  • Drug metabolism
  • E1A binding protein p300 (p300)
  • Nuclear receptor
  • Post-translational modification (PTM)
  • Pregnane X receptor (PXR)
  • Transcription regulation

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Genetics
  • Molecular Biology
  • Structural Biology

Cite this

Acetylation of lysine 109 modulates pregnane X receptor DNA binding and transcriptional activity. / Pasquel, Danielle; Doricakova, Aneta; Li, Hao; Kortagere, Sandhya; Krasowski, Matthew D.; Biswas, Arunima; Walton, William G.; Redinbo, Matthew R.; Dvorak, Zdenek; Mani, Sridhar.

In: Biochimica et Biophysica Acta - Gene Regulatory Mechanisms, 18.11.2015.

Research output: Contribution to journalArticle

Pasquel, Danielle ; Doricakova, Aneta ; Li, Hao ; Kortagere, Sandhya ; Krasowski, Matthew D. ; Biswas, Arunima ; Walton, William G. ; Redinbo, Matthew R. ; Dvorak, Zdenek ; Mani, Sridhar. / Acetylation of lysine 109 modulates pregnane X receptor DNA binding and transcriptional activity. In: Biochimica et Biophysica Acta - Gene Regulatory Mechanisms. 2015.
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AU - Krasowski, Matthew D.

AU - Biswas, Arunima

AU - Walton, William G.

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