Pregnane X Receptor (PXR), like other members of its class of nuclear receptors, undergoes posttranslational modification [PTM] (e.g., phosphorylation). However, it is unknown if acetylation (a major and common form of protein PTM) is observed on PXR and, if it is, whether it is of functional consequence. PXR has recently emerged as an important regulatory protein with multiple ligand-dependent functions. In the present work we show that PXR is indeed acetylated in vivo. SIRT1 (Sirtuin 1), a NAD-dependent class III histone deacetylase and a member of the sirtuin family of proteins, partially mediates deacetylation of PXR. Most importantly, the acetylation status of PXR regulates its selective function independent of ligand activation.
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.
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