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

Jae Min Yuk, 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

Research output: Contribution to journalReview articlepeer-review

160 Scopus citations

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.

Original languageEnglish
Pages (from-to)742-751
Number of pages10
JournalNature Immunology
Volume12
Issue number8
DOIs
StatePublished - Aug 2011

Bibliographical note

Funding Information:
We thank S.-Y. Choi for critical reading of manuscript; D.-H. Choi for technical assistance; E. Junn (University of New Jersey) for reagents; and J.-S. Kim and J.-W. Jang for support with total-body irradiation of mice for bone marrow transplantation. Supported by the National Research Foundation of Korea (Korean Ministry of Education, Science and Technology through the Infection Signaling Network Research Center (2011-0006228) at Chungnam National University), the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A100588) and the Korean Ministry of Education, Science and Technology (National Creative Research Initiatives Grant 20110018305).

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