Differential SUMOylation of LXRα and LXRβ Mediates Transrepression of STAT1 Inflammatory Signaling in IFN-γ-Stimulated Brain Astrocytes

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.

Poly(ADP-ribose) Polymerase 1 Represses Liver X Receptor-mediated ABCA1 Expression and Cholesterol Efflux in Macrophages

“…Here, we demonstrated that LXR␣ was PARylated by PARP-1. Several post-translational modifications on LXR␣ have been previously described including phosphorylation (28), O-linked ␤-N-acetylglucosamine (O-GlcNAcylation) (55), acetylation (37), and sumoylation (56). These modifications on LXR␣ were shown to impact target gene expression through changes in LXR␣ stability, transactivation, and/or recruitment of transcriptional regulatory factors at specific target genes.…”

SUMOylation of the Farnesoid X Receptor (FXR) Regulates the Expression of FXR Target Genes

“…RXR␣ as the obligate heterodimeric partner for FXR is also negatively regulated by SUMOylation (10). For example, there is recent evidence that SUMOylation of LXR␣ blocks the recruitment of RXR␣ to loci of LXR target genes (35)(36)(37). In addition to interference with interactions with coactivators, SUMOylation of NRs can also recruit corepressors such as RIP40 and the nuclear receptor corepressorhistone deacetylase (HDAC3) complex.…”

“…In addition to interference with interactions with coactivators, SUMOylation of NRs can also recruit corepressors such as RIP40 and the nuclear receptor corepressorhistone deacetylase (HDAC3) complex. Inhibition of corepressor release may also occur in a process called transrepression (4,36). Further studies will be required to define which of these or other mechanisms are operative in regulating the transcriptional activity of FXR.…”

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

“…PPAR and LXR can further inhibit corepressor clearance from NF-B by preventing proteasomal degradation of NcoR1 in a ligand-and SUMOylation dependent manner [201,202]. SUMOylation is also implicated in LXRmediated transrepression of STAT1 downstream of interferon signaling [203]. Furthermore, PPAR interacts with both c-jun and p65 to repress AP-1-and NF-B-driven gene expression, respectively [204].…”