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.

Nutritional status modifies pregnane X receptor regulated transcriptome

“…PXR also interacts with multiple transcription factors, such as forkhead box protein O1 (FOXO1) and sterol regulatory element-binding protein 1 (SREBP1), which are heavily regulated by energy homeostasis 6,12 . Furthermore, a cellular energy sensor sirtuin 1 interacts with and deacetylates PXR 11,13 , which may affect PXR dimerization and DNA binding 14 . Low glucose has been described to induce PXR Ser 350 phosphorylation in cell models 15 .…”

Phosphorylation Modulates the Coregulatory Protein Exchange of the Nuclear Receptor Pregnane X Receptor

“…This approach will allow us to continue to examine the myriad of PTMs on PXR moving forward in both cell-based and live animal models. The likely involvement of numerous PTMs in regulating the PXR transactivation and transrepression capacity has been highlighted in numerous recent studies (Biswas et al, 2011;Cui et al, 2015;Cui et al, 2016;Elias et al, 2014;Hu et al, 2010;Lichti-Kaiser et al, 2009a;Lichti-Kaiser et al, 2009b;Pasquel et al, 2016;Sugatani et al, 2016). The key PTMs described to date that regulate PXR biology include phosphorylation, acetylation, ubiquitination, and SUMOylation.…”

Fine tuning of vitamin D receptor (VDR) activity by post-transcriptional and post-translational modifications

“…Reaction that introduces an acetyl functional group into a molecule is termed acetylation. It is common modification in most nuclear receptors, including PXR [ 91 ], AR or ERα [ 92 ]. Surprisingly, there is no clear proof of VDR protein acetylation to this date.…”