Research ArticleBiochemistry

Small heterodimer partner SHP mediates liver X receptor (LXR)–dependent suppression of inflammatory signaling by promoting LXR SUMOylation specifically in astrocytes

See allHide authors and affiliations

Science Signaling  02 Aug 2016:
Vol. 9, Issue 439, pp. ra78
DOI: 10.1126/scisignal.aaf4850

You are currently viewing the abstract.

View Full Text

Log in to view the full text

Log in through your institution

Log in through your institution

SHP delivers SUMO to suppress inflammation

Inflammation contributes to various neurodegenerative diseases and occurs in response to brain injury. LXR transcriptional repressors suppress the expression of inflammatory genes. Lee et al. found that an orphan nuclear receptor called SHP (also known as NR0B2) facilitated the attachment of SUMO to LXRs specifically in astrocytes, either by acting as a bridge between LXRα and its SUMO-conjugating enzyme HDAC4 or by preventing the degradation of PIAS1, the SUMO-conjugating enzyme for LXRβ. The findings present opportunities for future drug development to limit neuroinflammation.


Liver X receptors (LXRs) suppress the expression of inflammatory genes in a context-specific manner. In astrocytes, SUMOylation of LXRs promotes their anti-inflammatory effects. We found that small heterodimer partner (SHP), also known as NR0B2 (nuclear receptor subfamily 0, group B, member 2), facilitates the anti-inflammatory actions of LXRs by promoting their SUMOylation. Knockdown of SHP abrogated SUMOylation of LXRs, preventing their anti-inflammatory effects, in primary rat astrocytes but not macrophages. The underlying mechanisms differed according to LXR isoform. SHP promoted SUMO2 and SUMO3 attachment to LXRα by interacting directly with the histone deacetylase and E3 SUMO ligase HDAC4. In contrast, SHP promoted SUMO1 attachment to LXRβ by stabilizing the E3 SUMO ligase PIAS1. SHP bound PIAS1 and disrupted its interaction with the E3 ubiquitin ligase SIAH1. Knocking down SIAH1 rescued LXRβ SUMOylation in SHP-deficient astrocytes. Our data collectively suggested that SHP mediates the anti-inflammatory actions of LXRs through differential regulation of receptor SUMOylation specifically in astrocytes, thereby revealing potential avenues for therapeutic development in diseases associated with brain inflammation.

View Full Text

Stay Connected to Science Signaling