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 a [RXRa; 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, RXRa undergoes rapid post-translational modifications, including c-Jun N-terminal kinase (JNK)-mediated phosphorylation, which correlates with a reduction in RXRa function. A small ubiquitin-like modifier (SUMO) acceptor site was recently described in human RXRa, yet the contributors, regulators, and consequences of SUMO-RXRa 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 RXRa directly, remain unexplored. We sought to determine if inflammation induces SUMOylation of RXRa in human liver-derived (HuH-7) cells. Lipopolysaccharide, interleukin-1b, and tumor necrosis factor a (TNFa) rapidly and substantially stimulated SUMOylation of RXRa. Two RXRa ligands, 9-cis retinoic acid (9cRA) and LG268, induced SUMOylation of RXRa, whereas both inflammation-and ligand-induced SUMOylation of RXRa require the K108 residue. Pretreatment with 1,9-pyrazoloanthrone (SP600125), a potent JNK inhibitor, abrogates TNFa-and 9cRA-stimulated RXRa SUMOylation. Pretreatment with SUMOylation inhibitors markedly augmented basal expression of several RXRa-regulated hepatobiliary genes. These results indicate that inflammatory signaling pathways rapidly induce SUMOylation of RXRa, adding to the repertoire of RXRa molecular species in the hepatocyte that respond to inflammation. SUMOylation, a newly described post-translational modification of RXRa, appears to contribute to the inflammation-induced reduction of RXRaregulated gene expression in the liver that affects core hepatic functions, including hepatobiliary transport.

SUMOylation and Ubiquitylation Circuitry Controls Pregnane X Receptor Biology in Hepatocytes

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14-3-3 Binding and Sumoylation Concur to the Down-Modulation of β-catenin Antagonist chibby 1 in Chronic Myeloid Leukemia

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SUMOylation: Novel Neuroprotective Approach for Alzheimer’s Disease?

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