Nuclear Export of Retinoid X Receptor Alpha in Response to Interleukin-1beta-mediated Cell Signaling: Roles for Jnk and Ser260.
From: Texas Children’s Liver Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
The Journal of biological chemistry
- Publish Date: Jun 2006
- ISSN: 0021-9258
- Volume: 281
- Issue: 22
- Pages: 15434-40
- Medium: Print
- Language: English
- Citation (JAMA): Zimmerman Tracy L, Thevananther Sundararajah, Ghose Romi, et al. Nuclear Export of Retinoid X Receptor Alpha in Response to Interleukin-1beta-mediated Cell Signaling: Roles for Jnk and Ser260.. J. Biol. Chem. Jun 2006;281:15434-40
Abstract
As the obligate heterodimer partner to class II nuclear receptors, the retinoid X receptor alpha (RXRalpha) plays a vital physiological role in the regulation of multiple hepatic functions, including bile formation, intermediary metabolism, and endobiotic/xenobiotic detoxification. Many RXRalpha-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 RXRalpha, generally considered a stable nuclear resident protein, undergoes rapid nuclear export in response to signals initiated by the pro-inflammatory cytokine interleukin-1beta (IL-1beta), a central activator of the acute phase response. Within 30 min of exposure to IL-1beta, nuclear levels of RXRalpha are markedly suppressed in human liver-derived HepG2 cells, temporally coinciding with its appearance in the cytoplasm. The nuclear residence of RXRalpha 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-1beta-mediated reductions in nuclear RXRalpha 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 RXRalpha function, as critical for IL-1beta-mediated nuclear export of transfected human RXRalpha-green fluorescent fusion constructs. These findings indicate that inflammation-mediated cell signaling leads to rapid and profound reductions in nuclear RXRalpha levels, via a multistep, JNK-dependent mechanism involving Ser260, nuclear export, and proteasomal degradation. Thus, inflammation-meditated cell signaling targets RXRalpha for nuclear export and degradation; a potential mechanism that explains the broad suppression of RXRalpha-dependent gene expression in the inflamed liver.
Mesh Headings (Keywords): Active Transport, Cell Nucleus, Amino Acid Substitution, Base Sequence, Binding Sites, Cell Line, DNA, Humans, Interleukin-1, JNK Mitogen-Activated Protein Kinases, Models, Biological, Mutagenesis, Site-Directed, Recombinant Fusion Proteins, Retinoid X Receptor alpha, Serine, Signal Transduction, Transfection
Check for Full Text / PubMed Unique Identifier (PMID): 16551633
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