Nuclear export of retinoid X receptor α in response to interleukin-1β-mediated cell signaling -: Roles for JNK and Ser260

As the obligate heterodimer partner to class II nuclear receptors, the retinoid X receptor alpha( RXR alpha) plays a vital physiological role in the regulation of multiple hepatic functions, including bile formation, intermediary metabolism, and endobiotic/xenobiotic detoxification. Many RXR alpha-regulated genes are themselves suppressed in inflamed liver via unknown mechanisms, which constitute a substantial component of the negative hepatic acute phase response. In this study we show that RXR alpha, generally considered a stable nuclear resident protein, undergoes rapid nuclear export in response to signals initiated by the pro-inflammatory cytokine interleukin-1 beta( IL-1 beta), a central activator of the acute phase response. Within 30 min of exposure to IL-1 beta, nuclear levels of RXR alpha are markedly suppressed in human liver-derived HepG2 cells, temporally coinciding with its appearance in the cytoplasm. The nuclear residence of RXR alpha is maintained by inhibiting c-jun N-terminal kinase ( JNK, curcumin or SP600125) or CRM-1-mediated nuclear export ( Leptomycin B). Pretreatment with the proteasome inhibitor MG132 blocks IL-1 beta-mediated reductions in nuclear RXR alpha levels while increasing accumulation in the cytoplasm. Mutational studies identify one residue, serine 260, a JNK phosphoacceptor site whose phosphorylation status had an unknown role in RXR alpha function, as critical for IL-1 beta-mediated nuclear export of transfected human RXR alpha-green fluorescent fusion constructs. These findings indicate that inflammation-mediated cell signaling leads to rapid and profound reductions in nuclear RXR alpha levels, via a multistep, JNK-dependent mechanism involving Ser260, nuclear export, and proteasomal degradation. Thus, inflammation-meditated cell signaling targets RXR alpha for nuclear export and degradation; a potential mechanism that explains the broad suppression of RXR alpha-dependent gene expression in the inflamed liver.