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Small heterodimer partner interacts with NLRP3 and negatively regulates activation of the NLRP3 inflammasome

Author

Listed:
  • Chul-Su Yang

    (Chungnam National University School of Medicine
    Infection Signaling Network Research Center, Chungnam National University School of Medicine
    College of Science and Technology, Hanyang University)

  • Jwa-Jin Kim

    (Chungnam National University School of Medicine
    Infection Signaling Network Research Center, Chungnam National University School of Medicine
    College of Medicine, Konyang University)

  • Tae Sung Kim

    (Chungnam National University School of Medicine
    Infection Signaling Network Research Center, Chungnam National University School of Medicine)

  • Phil Young Lee

    (Medical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology)

  • Soo Yeon Kim

    (Chungnam National University School of Medicine
    Infection Signaling Network Research Center, Chungnam National University School of Medicine)

  • Hye-Mi Lee

    (Chungnam National University School of Medicine
    Infection Signaling Network Research Center, Chungnam National University School of Medicine)

  • Dong-Min Shin

    (Chungnam National University School of Medicine
    Infection Signaling Network Research Center, Chungnam National University School of Medicine)

  • Loi T. Nguyen

    (Infection and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology)

  • Moo-Seung Lee

    (Infection and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology)

  • Hyo Sun Jin

    (Chungnam National University School of Medicine
    Infection Signaling Network Research Center, Chungnam National University School of Medicine)

  • Kwang-Kyu Kim

    (College of Life Science, Daejeon University)

  • Chul-Ho Lee

    (Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology)

  • Myung Hee Kim

    (Infection and Immunity Research Center, Korea Research Institute of Bioscience and Biotechnology)

  • Sung Goo Park

    (Medical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology)

  • Jin-Man Kim

    (Infection Signaling Network Research Center, Chungnam National University School of Medicine)

  • Hueng-Sik Choi

    (National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University)

  • Eun-Kyeong Jo

    (Chungnam National University School of Medicine
    Infection Signaling Network Research Center, Chungnam National University School of Medicine)

Abstract

Excessive activation of the NLRP3 inflammasome results in damaging inflammation, yet the regulators of this process remain poorly defined. Herein, we show that the orphan nuclear receptor small heterodimer partner (SHP) is a negative regulator of NLRP3 inflammasome activation. NLRP3 inflammasome activation leads to an interaction between SHP and NLRP3, proteins that are both recruited to mitochondria. Overexpression of SHP competitively inhibits binding of NLRP3 to apoptosis-associated speck-like protein containing a CARD (ASC). SHP deficiency results in increased secretion of proinflammatory cytokines IL-1β and IL-18, and excessive pathologic responses typically observed in mouse models of kidney tubular necrosis and peritoneal gout. Notably, the loss of SHP results in accumulation of damaged mitochondria and a sustained interaction between NLRP3 and ASC in the endoplasmic reticulum. These data are suggestive of a role for SHP in controlling NLRP3 inflammasome activation through a mechanism involving interaction with NLRP3 and maintenance of mitochondrial homeostasis.

Suggested Citation

  • Chul-Su Yang & Jwa-Jin Kim & Tae Sung Kim & Phil Young Lee & Soo Yeon Kim & Hye-Mi Lee & Dong-Min Shin & Loi T. Nguyen & Moo-Seung Lee & Hyo Sun Jin & Kwang-Kyu Kim & Chul-Ho Lee & Myung Hee Kim & Sun, 2015. "Small heterodimer partner interacts with NLRP3 and negatively regulates activation of the NLRP3 inflammasome," Nature Communications, Nature, vol. 6(1), pages 1-11, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7115
    DOI: 10.1038/ncomms7115
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