title: Inflammatory mediators increase SUMOylation of retinoid X receptor α in a c-Jun N-terminal kinase-dependent manner in human hepatocellular carcinoma cells.
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.
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schneider Aguirre
authors.forename: Saul J
authors.initials: SJ
authors.lastname: Karpen
mesh_terms: D000077556:Alitretinoin; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009930:Organic Chemicals / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D047490:Retinoid X Receptor alpha / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D058207:Sumoylation / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D018836:Inflammation Mediators; D053583:Interleukin-1beta; C423914:LG 268; D008024:Ligands; D009930:Organic Chemicals; D018160:Receptors, Cytoplasmic and Nuclear; D047490:Retinoid X Receptor alpha; D025841:Small Ubiquitin-Related Modifier Proteins; D014409:Tumor Necrosis Factor-alpha; D000077556:Alitretinoin; D014212:Tretinoin; D048031:JNK Mitogen-Activated Protein Kinases