Abstract
Retinoid X receptor α [RXRα; nuclear receptor (NR)2B1] is a crucial regulator in the expression of a broad array of hepatic genes under both normal and pathologic conditions. During inflammation, RXRα undergoes rapid post-translational modifications, including c-Jun N-terminal kinase (JNK)-mediated phosphorylation, which correlates with a reduction in RXRα function. A small ubiquitin-like modifier (SUMO) acceptor site was recently described in human RXRα, yet the contributors, regulators, and consequences of SUMO-RXRα are not well understood. Inflammation and other stressors alter nuclear receptor function in liver and induce SUMOylation of several NRs as part of proinflammatory gene regulation, but linkages between these two pathways in liver, or for RXRα directly, remain unexplored. We sought to determine if inflammation induces SUMOylation of RXRα in human liver-derived (HuH-7) cells. Lipopolysaccharide, interleukin-1β, and tumor necrosis factor α (TNFα) rapidly and substantially stimulated SUMOylation of RXRα. Two RXRα ligands, 9-cis retinoic acid (9cRA) and LG268, induced SUMOylation of RXRα, whereas both inflammation- and ligand-induced SUMOylation of RXRα require the K108 residue. Pretreatment with 1,9-pyrazoloanthrone (SP600125), a potent JNK inhibitor, abrogates TNFα- and 9cRA-stimulated RXRα SUMOylation. Pretreatment with SUMOylation inhibitors markedly augmented basal expression of several RXRα-regulated hepatobiliary genes. These results indicate that inflammatory signaling pathways rapidly induce SUMOylation of RXRα, adding to the repertoire of RXRα molecular species in the hepatocyte that respond to inflammation. SUMOylation, a newly described post-translational modification of RXRα, appears to contribute to the inflammation-induced reduction of RXRα-regulated gene expression in the liver that affects core hepatic functions, including hepatobiliary transport.
Footnotes
- Received February 11, 2013.
- Accepted May 20, 2013.
↵1 Current affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
This work was supported by grants from National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK56239]; the Texas Gulf Coast Digestive Disease Center [Grant DK56338]; and the Medical Scientist Training Program Grant [T32GM007330-34].
Portions of this work were previously presented at the following meeting: Aguirre RS and Karpen SJ (2010) Inflammation-associated SUMOylation of hepatic RXRα: a new modification of a central liver gene regulator. American Association for the Study of Liver Diseases; 2010 Oct 29–Nov 2; Boston, MA (abstract 588).
Aguirre RS (2011) SUMOylation of Liver RXRα: A New Modification of a Central Liver Gene Regulator. Doctoral dissertation, Baylor College of Medicine, Houston, TX.
This article has supplemental material available at molpharm.aspetjournals.org.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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