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J. Biol. Chem., Vol. 281, Issue 22, 15434-15440, June 2, 2006

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Nuclear Export of Retinoid X Receptor in Response to Interleukin-1-mediated Cell Signaling

ROLES FOR JNK AND SER^260*

From the Texas Children's Liver Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030

As the obligate heterodimer partner to class II nuclear receptors, the retinoid X receptor (RXR) plays a vital physiological role in the regulation of multiple hepatic functions, including bile formation, intermediary metabolism, and endobiotic/xenobiotic detoxification. Many RXR-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, generally considered a stable nuclear resident protein, undergoes rapid nuclear export in response to signals initiated by the pro-inflammatory cytokine interleukin-1 (IL-1), a central activator of the acute phase response. Within 30 min of exposure to IL-1, nuclear levels of RXR are markedly suppressed in human liver-derived HepG2 cells, temporally coinciding with its appearance in the cytoplasm. The nuclear residence of RXR 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-mediated reductions in nuclear RXR 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 function, as critical for IL-1-mediated nuclear export of transfected human RXR-green fluorescent fusion constructs. These findings indicate that inflammation-mediated cell signaling leads to rapid and profound reductions in nuclear RXR levels, via a multistep, JNK-dependent mechanism involving Ser²⁶⁰, nuclear export, and proteasomal degradation. Thus, inflammation-meditated cell signaling targets RXR for nuclear export and degradation; a potential mechanism that explains the broad suppression of RXR-dependent gene expression in the inflamed liver.

Received for publication, August 28, 2005 , and in revised form, March 6, 2006.

^* A portion of this work was presented in abstract form at the 2004 annual meeting of the American Association for the Study of Liver Diseases (AASLD). This work was supported by Grants AI46773 (to A. R. B.), DK56239 (to S. J. K.), and DK56338 (supporting the Texas Gulf Coast Digestive Diseases Center) from the National Institutes of Health and the Texas Children's Hospital Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: TX Children's Liver Center, Dept. of Pediatrics/GI, Hepatology & Nutrition, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Tel.: 832-824-3754; Fax: 832-825-4893; E-mail: skarpen{at}bcm.tmc.edu.

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