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

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, 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

Department of Life Science

Research output: Contribution to journal › Review article › peer-review

167 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 language	English
Pages (from-to)	742-751
Number of pages	10
Journal	Nature Immunology
Volume	12
Issue number	8
DOIs	https://doi.org/10.1038/ni.2064
State	Published - 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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Yuk, J. M., Shin, D. M., Lee, H. M., Kim, J. J., Kim, S. W., Jin, H. S., Yang, C. S., Park, K. A., Chanda, D., Kim, D. K., Huang, S. M., Lee, S. K., Lee, C. H., Kim, J. M., Song, C. H., Lee, S. Y., Hur, G. M., Moore, D. D., Choi, H. S., & Jo, E. K. (2011). The orphan nuclear receptor SHP acts as a negative regulator in inflammatory signaling triggered by Toll-like receptors. Nature Immunology, 12(8), 742-751. https://doi.org/10.1038/ni.2064

@article{49f86d9b04df4ec3baf53f15a27ac6e6,

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

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.",

author = "Yuk, {Jae Min} and Shin, {Dong Min} and Lee, {Hye Mi} and Kim, {Jwa Jin} and Kim, {Sun Woong} and Jin, {Hyo Sun} and Yang, {Chul Su} and Park, {Kyeong Ah} and Dipanjan Chanda and Kim, {Don Kyu} and Huang, {Song Mei} and Lee, {Sang Ki} and Lee, {Chul Ho} and Kim, {Jin Man} and Song, {Chang Hwa} and Lee, {Soo Young} and Hur, {Gang Min} and Moore, {David D.} and Choi, {Hueng Sik} and Jo, {Eun Kyeong}",

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).",

year = "2011",

month = aug,

doi = "10.1038/ni.2064",

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Yuk, JM, Shin, DM, Lee, HM, Kim, JJ, Kim, SW, Jin, HS, Yang, CS, Park, KA, Chanda, D, Kim, DK, Huang, SM, Lee, SK, Lee, CH, Kim, JM, Song, CH, Lee, SY, Hur, GM, Moore, DD, Choi, HS & Jo, EK 2011, 'The orphan nuclear receptor SHP acts as a negative regulator in inflammatory signaling triggered by Toll-like receptors', Nature Immunology, vol. 12, no. 8, pp. 742-751. https://doi.org/10.1038/ni.2064

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AU - Yuk, Jae Min

AU - Shin, Dong Min

AU - Lee, Hye Mi

AU - Kim, Jwa Jin

AU - Kim, Sun Woong

AU - Jin, Hyo Sun

AU - Yang, Chul Su

AU - Park, Kyeong Ah

AU - Chanda, Dipanjan

AU - Kim, Don Kyu

AU - Huang, Song Mei

AU - Lee, Sang Ki

AU - Lee, Chul Ho

AU - Kim, Jin Man

AU - Song, Chang Hwa

AU - Lee, Soo Young

AU - Hur, Gang Min

AU - Moore, David D.

AU - Choi, Hueng Sik

AU - Jo, Eun Kyeong

N1 - 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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AB - 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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DO - 10.1038/ni.2064

M3 - Review article

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SN - 1529-2908

VL - 12

SP - 742

EP - 751

JO - Nature Immunology

JF - Nature Immunology

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ER -

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

Abstract

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