Inflammatory mediators increase SUMOylation of retinoid X receptor ? in a c-Jun N-terminal kinase-dependent manner in human hepatocellular carcinoma cells.
Ontology highlight
ABSTRACT: Retinoid X receptor ? [RXR?; 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, RXR? undergoes rapid post-translational modifications, including c-Jun N-terminal kinase (JNK)-mediated phosphorylation, which correlates with a reduction in RXR? function. A small ubiquitin-like modifier (SUMO) acceptor site was recently described in human RXR?, yet the contributors, regulators, and consequences of SUMO-RXR? 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 RXR? directly, remain unexplored. We sought to determine if inflammation induces SUMOylation of RXR? in human liver-derived (HuH-7) cells. Lipopolysaccharide, interleukin-1?, and tumor necrosis factor ? (TNF?) rapidly and substantially stimulated SUMOylation of RXR?. Two RXR? ligands, 9-cis retinoic acid (9cRA) and LG268, induced SUMOylation of RXR?, whereas both inflammation- and ligand-induced SUMOylation of RXR? require the K108 residue. Pretreatment with 1,9-pyrazoloanthrone (SP600125), a potent JNK inhibitor, abrogates TNF?- and 9cRA-stimulated RXR? SUMOylation. Pretreatment with SUMOylation inhibitors markedly augmented basal expression of several RXR?-regulated hepatobiliary genes. These results indicate that inflammatory signaling pathways rapidly induce SUMOylation of RXR?, adding to the repertoire of RXR? molecular species in the hepatocyte that respond to inflammation. SUMOylation, a newly described post-translational modification of RXR?, appears to contribute to the inflammation-induced reduction of RXR?-regulated gene expression in the liver that affects core hepatic functions, including hepatobiliary transport.
SUBMITTER: Schneider Aguirre R
PROVIDER: S-EPMC3716323 | biostudies-literature | 2013 Aug
REPOSITORIES: biostudies-literature
ACCESS DATA
