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Differential SUMOylation of LXRalpha and LXRbeta mediates transrepression of STAT1 inflammatory signaling in IFN-gamma-stimulated brain astrocytes.

Lee, JH; Park, SM; Kim, OS; Lee, CS; Woo, JH; Park, SJ; Joe, EH; Jou, I
Molecular cell, 35(6):806-817, 2009
Journal Title
Molecular cell
To unravel the roles of LXRs in inflammation and immunity, we examined the function of LXRs in development of IFN-gamma-mediated inflammation using cultured rat brain astrocytes. LXR ligands inhibit neither STAT1 phosphorylation nor STAT1 translocation to the nucleus but, rather, inhibit STAT1 binding to promoters and the expression of IRF1, TNFalpha, and IL-6, downstream effectors of STAT1 action. Immunoprecipitation data revealed that LXRbeta formed a trimer with PIAS1-pSTAT1, whereas LXRalpha formed a trimer with HDAC4-pSTAT1, mediated by direct ligand binding to the LXR proteins. In line with the fact that both PIAS1 and HDAC4 belong to the SUMO E3 ligase family, LXRbeta and LXRalpha were SUMO-conjugated by PIAS1 or HDAC4, respectively, and SUMOylation was blocked by transient transfection of appropriate individual siRNAs, reversing LXR-induced suppression of IRF1 and TNFalpha expression. Together, our data show that SUMOylation is required for the suppression of STAT1-dependent inflammatory responses by LXRs in IFN-gamma-stimulated brain astrocytes.
MeSH terms
Active Transport, Cell NucleusAnimalsAnimals, NewbornAstrocytes/metabolism*Binding SitesCells, CulturedDNA-Binding Proteins/geneticsDNA-Binding Proteins/metabolism*Histone Deacetylases/metabolismInflammation/geneticsInflammation/metabolism*Inflammation/prevention & controlInflammation Mediators/metabolism*Interferon Regulatory Factor-1/metabolismInterferon-gamma/metabolism*Interleukin-6/metabolismLigandsOrphan Nuclear ReceptorsPhosphorylationPromoter Regions, GeneticProtein Inhibitors of Activated STAT/metabolismProtein Processing, Post-Translational*RNA InterferenceRatsRats, Sprague-DawleyReceptors, Cytoplasmic and Nuclear/geneticsReceptors, Cytoplasmic and Nuclear/metabolism*STAT1 Transcription Factor/geneticsSTAT1 Transcription Factor/metabolism*Signal TransductionSmall Ubiquitin-Related Modifier Proteins/metabolism*TransfectionTumor Necrosis Factor-alpha/metabolism
Appears in Collections:
Journal Papers > Research Organization > Chronic Inflammatory Disease Research Center
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
AJOU Authors
이, 지훈박, 상면우, 주홍박, 수정조, 은혜주, 일로
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