Differential SUMOylation of LXRalpha and LXRbeta Mediates Transrepression of STAT1 Inflammatory Signaling in IFN-gamma-stimulated Brain Astrocytes

Mol Cell. 2009 Sep 24;35(6):806-17. doi: 10.1016/j.molcel.2009.07.021.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Animals, Newborn
  • Astrocytes / metabolism*
  • Binding Sites
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Histone Deacetylases / metabolism
  • Inflammation / genetics
  • Inflammation / metabolism*
  • Inflammation / prevention & control
  • Inflammation Mediators / metabolism*
  • Interferon Regulatory Factor-1 / metabolism
  • Interferon-gamma / metabolism*
  • Interleukin-6 / metabolism
  • Ligands
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Inhibitors of Activated STAT / metabolism
  • Protein Processing, Post-Translational*
  • RNA Interference
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism*
  • Signal Transduction
  • Small Ubiquitin-Related Modifier Proteins / metabolism*
  • Transfection
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • DNA-Binding Proteins
  • Inflammation Mediators
  • Interferon Regulatory Factor-1
  • Interleukin-6
  • Ligands
  • Liver X Receptors
  • Nr1h3 protein, rat
  • Orphan Nuclear Receptors
  • Protein Inhibitors of Activated STAT
  • Receptors, Cytoplasmic and Nuclear
  • STAT1 Transcription Factor
  • Small Ubiquitin-Related Modifier Proteins
  • Stat1 protein, rat
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • Histone Deacetylases