title: A SUMO-acetyl switch in PXR biology.
abstract: Post-translational modification (PTM) of nuclear receptor superfamily members regulates various aspects of their biology to include sub-cellular localization, the repertoire of protein-binding partners, as well as their stability and mode of degradation. The nuclear receptor pregnane X receptor (PXR, NR1I2) is a master-regulator of the drug-inducible gene expression in liver and intestine. The PXR-mediated gene activation program is primarily recognized to increase drug metabolism, drug transport, and drug efflux pathways in these tissues. The activation of PXR also has important implications in significant human diseases including inflammatory bowel disease and cancer. Our recent investigations reveal that PXR is modified by multiple PTMs to include phosphorylation, SUMOylation, and ubiquitination. Using both primary cultures of hepatocytes and cell-based assays, we show here that PXR is modified through acetylation on lysine residues. Further, we show that increased acetylation of PXR stimulates its increased SUMO-modification to support active transcriptional suppression. Pharmacologic inhibition of lysine de-acetylation using trichostatin A (TSA) alters the sub-cellular localization of PXR in cultured hepatocytes, and also has a profound impact upon PXR transactivation capacity. Both the acetylation and SUMOylation status of the PXR protein is affected by its ability to associate with the lysine de-acetylating enzyme histone de-acetylase (HDAC)3 in a complex with silencing mediator of retinoic acid and thyroid hormone receptor (SMRT). Taken together, our data support a model in which a SUMO-acetyl 'switch' occurs such that acetylation of PXR likely stimulates SUMO-modification of PXR to promote the active repression of PXR-target gene expression. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.
authors.affiliation: Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, United States.
authors.forename: Wenqi
authors.initials: W
authors.lastname: Cui
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, CA, United States.
authors.forename: Mengxi
authors.initials: M
authors.lastname: Sun
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Shupei
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, United States.
authors.forename: Xunan
authors.initials: X
authors.lastname: Shen
authors.affiliation: Mass Spectrometry Lab (N.G. and T.D.W.), University of Kansas, Lawrence, KS, United States.
authors.forename: Nadezhda
authors.initials: N
authors.lastname: Galeva
authors.affiliation: Mass Spectrometry Lab (N.G. and T.D.W.), University of Kansas, Lawrence, KS, United States.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Williams
authors.affiliation: Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, United States. Electronic address: stauding@ku.edu.
authors.forename: Jeff L
authors.initials: JL
authors.lastname: Staudinger
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D017930:Genes, Reporter; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics / Q000378:metabolism*; D000077297:Pregnane X Receptor; D061251:Primary Cell Culture; D011499:Protein Processing, Post-Translational; D011987:Receptors, Steroid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D058207:Sumoylation; D015533:Transcriptional Activation / Q000187:drug effects; D054875:Ubiquitination; D000099186:Histone Deacetylase 3
chemical_list: D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D008156:Luciferases; D008239:Lysine; D056985:Nuclear Receptor Co-Repressor 2; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D000099186:Histone Deacetylase 3; C000625852:NR1I2 protein, human; C539131:Ncor2 protein, mouse; C000625853:Nr1i2 protein, mouse; C012589:trichostatin A
keywords: Acetylation; Histone deacetylase 3; Nuclear receptor; Post-translational modification; Pregnane X receptor; SUMOylation; Silencing mediator of retinoic acid and thyroid hormone receptor; Ubiquitination