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

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

Jae-Min Yuk  1 , Dong-Min Shin, Hye-Mi Lee, Jwa-Jin Kim, Sun-Woong Kim, Hyo Sun Jin, Chul-Su Yang, Kyeong Ah Park, Dipanjan Chanda, Don-Kyu Kim, Song Mei Huang, Sang Ki Lee, Chul-Ho Lee, Jin-Man Kim, Chang-Hwa Song, Soo Young Lee, Gang Min Hur, David D Moore, Hueng-Sik Choi, Eun-Kyeong Jo
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The orphan nuclear receptor SHP acts as a negative regulator in inflammatory signaling triggered by Toll-like receptors

Jae-Min Yuk et al. Nat Immunol. .

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.

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