The orphan nuclear receptor SHP acts as a negative regulator in inflammatory signaling triggered by Toll-like receptors

Nat Immunol. 2011 Jul 3;12(8):742-51. doi: 10.1038/ni.2064.

Abstract

The orphan nuclear receptor SHP (small heterodimer partner) is a transcriptional corepressor that regulates hepatic metabolic pathways. Here we identified a role for SHP as an intrinsic negative regulator of Toll-like receptor (TLR)-triggered inflammatory responses. SHP-deficient mice were more susceptible to endotoxin-induced sepsis. SHP had dual regulatory functions in a canonical transcription factor NF-κB signaling pathway, acting as both a repressor of transactivation of the NF-κB subunit p65 and an inhibitor of polyubiquitination of the adaptor TRAF6. SHP-mediated inhibition of signaling via the TLR was mimicked by macrophage-stimulating protein (MSP), a strong inducer of SHP expression, via an AMP-activated protein kinase-dependent signaling pathway. Our data identify a previously unrecognized role for SHP in the regulation of TLR signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / immunology
  • Animals
  • Chromatin Immunoprecipitation
  • Female
  • Immunoblotting
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / immunology*
  • Receptors, Cytoplasmic and Nuclear / immunology*
  • Sepsis / immunology*
  • Signal Transduction
  • TNF Receptor-Associated Factor 6 / immunology
  • Toll-Like Receptors / immunology*
  • Ubiquitination / immunology

Substances

  • NF-kappa B
  • Receptors, Cytoplasmic and Nuclear
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptors
  • nuclear receptor subfamily 0, group B, member 2
  • AMP-Activated Protein Kinases