The orphan nuclear receptor SHP acts as a negative regulator in inflammatory signaling triggered by Toll-like receptors.
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.
Mesh Terms:
AMP-Activated Protein Kinases, Animals, Chromatin Immunoprecipitation, Female, Immunoblotting, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B, Receptors, Cytoplasmic and Nuclear, Sepsis, Signal Transduction, TNF Receptor-Associated Factor 6, Toll-Like Receptors, Ubiquitination
AMP-Activated Protein Kinases, Animals, Chromatin Immunoprecipitation, Female, Immunoblotting, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B, Receptors, Cytoplasmic and Nuclear, Sepsis, Signal Transduction, TNF Receptor-Associated Factor 6, Toll-Like Receptors, Ubiquitination
Nat. Immunol.
Date: Aug. 01, 2011
PubMed ID: 21725320
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