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

Nature Immunology volume 12, pages 742–751 (2011)Cite this article

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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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Figure 1: SHP protects against LPS-induced lethal shock through the inhibition of inflammatory responses in vivo.
Figure 2: SHP inhibits LPS-induced inflammatory responses in macrophages and splenocytes.
Figure 3: SHP is a regulator of signaling by Nod2 and RLRs but not of dectin-1 signaling.
Figure 4: SHP regulates TLR4-mediated NF-κB signaling through an interaction between SHP and p65.
Figure 5: SHP interacts with TRAF6 to negatively modulate its ubiquitination.
Figure 6: TLR4 activation induces SHP expression in macrophages via Ca2+-dependent activation of AMPK.
Figure 7: MSP-induced SHP regulates TLR4-mediated proinflammatory signaling through the activation of an LKB1-dependent AMPK pathway.

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Acknowledgements

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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Author notes

  1. Chul-Su Yang

    Present address: Present address: Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, California, USA.,

  2. Jae-Min Yuk and Dong-Min Shin: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology, Chungnam National University School of Medicine, Daejeon, South Korea

    Jae-Min Yuk, Dong-Min Shin, Hye-Mi Lee, Jwa-Jin Kim, Sun-Woong Kim, Hyo Sun Jin, Chul-Su Yang, Chang-Hwa Song & Eun-Kyeong Jo

  2. Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, South Korea

    Jae-Min Yuk, Dong-Min Shin, Hye-Mi Lee, Jwa-Jin Kim, Hyo Sun Jin, Chul-Su Yang, Kyeong Ah Park, Song Mei Huang, Jin-Man Kim, Gang Min Hur & Eun-Kyeong Jo

  3. Department of Pharmacology, Chungnam National University School of Medicine, Daejeon, South Korea

    Kyeong Ah Park & Gang Min Hur

  4. National Creative Research Initiatives Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, South Korea

    Dipanjan Chanda, Don-Kyu Kim & Hueng-Sik Choi

  5. Department of Pathology, Chungnam National University School of Medicine, Daejeon, South Korea

    Song Mei Huang & Jin-Man Kim

  6. Department of Sports Science, College of Natural Science, Chungnam National University, Daejeon, South Korea

    Sang Ki Lee

  7. Animal Model Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea

    Chul-Ho Lee

  8. Department of Bioinspired Science, College of Life Science, Ewha Womans University, Seoul, South Korea

    Soo Young Lee

  9. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

    David D Moore

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Contributions

J.-M.Y., D.-M.S., H.-M.L., S.-W.K, H.S.J., C.-S.Y., D.C., D.-K.K., S.M.H. and S.K.L. planned and did experiments and analyzed data; J.-J.K. and C.-H.S. planned and did most of the bone marrow–chimera experiments; K.A.P. and G.M.H. planned and did ubiquitination experiments; C.-H.L., J.-M.K., S.Y.L. and D.D.M. contributed to some of the experiments; H.-S.C. and E.-K.J. supervised the project, designed experiments and wrote the manuscript with comments from the coauthors; and all authors collaborated on the work.

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Correspondence to Hueng-Sik Choi or Eun-Kyeong Jo.

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Yuk, JM., Shin, DM., Lee, HM. et al. The orphan nuclear receptor SHP acts as a negative regulator in inflammatory signaling triggered by Toll-like receptors. Nat Immunol 12, 742–751 (2011). https://doi.org/10.1038/ni.2064

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