Abstract
Retinoid X Receptor α (RXRα; NR2B1) is a crucial regulator in the expression of a broad array of hepatic genes under both normal and pathological 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 has been 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 pro-inflammatory 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 (LPS), interleukin-1β (IL-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, while both inflammation- and ligand-induced SUMOylation of RXRα require the K108 residue. Pretreatment with 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.
- MAP kinases
- Sumoylation
- Jun Kinase
- Regulation of gene expression
- Liver transporters
- Transcription targets
- The American Society for Pharmacology and Experimental Therapeutics