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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 742751 (2011) | Download Citation

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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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).

Author information

Author notes

    • Chul-Su Yang

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

    • Jae-Min Yuk
    •  & Dong-Min Shin

    These authors contributed equally to this work.

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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

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

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DOI

https://doi.org/10.1038/ni.2064