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Toll-like receptor 9 protects non-immune cells from stress by modulating mitochondrial ATP synthesis through the inhibition of SERCA2

Author

Listed:
  • Yasunori Shintani

    (Queen Mary University of London
    Osaka University Graduate School of Medicine)

  • Hannes CA Drexler

    (Max Planck Institute for Molecular Biomedicine)

  • Hidetaka Kioka

    (Osaka University Graduate School of Medicine)

  • Cesare MN Terracciano

    (Imperial College London, National Heart & Lung Institute, Hammersmith Campus)

  • Steven R Coppen

    (Queen Mary University of London)

  • Hiromi Imamura

    (Kyoto University Science Frontier Laboratory building Room 305)

  • Masaharu Akao

    (National Hospital Organization Kyoto Medical Center)

  • Junichi Nakai

    (Saitama University Brain Science Institute)

  • Ann P Wheeler

    (Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London)

  • Shuichiro Higo

    (Osaka University Graduate School of Medicine)

  • Hiroyuki Nakayama

    (Osaka University Graduate School of Pharmaceutical Sciences)

  • Seiji Takashima

    (Osaka University Graduate School of Medicine
    Osaka University Graduate School of Medicine)

  • Kenta Yashiro

    (Queen Mary University of London)

  • Ken Suzuki

    (Queen Mary University of London)

Abstract

Toll-like receptor 9 (TLR9) has a key role in the recognition of pathogen DNA in the context of infection and cellular DNA that is released from damaged cells. Pro-inflammatory TLR9 signalling pathways in immune cells have been well investigated, but we have recently discovered an alternative pathway in which TLR9 temporarily reduces energy substrates to induce cellular protection from stress in cardiomyocytes and neurons. However, the mechanism by which TLR9 stimulation reduces energy substrates remained unknown. Here, we identify the calcium-transporting ATPase, SERCA2 (also known as Atp2a2), as a key molecule for the alternative TLR9 signalling pathway. TLR9 stimulation reduces SERCA2 activity, modulating Ca2+ handling between the SR/ER and mitochondria, which leads to a decrease in mitochondrial ATP levels and the activation of cellular protective machinery. These findings reveal how distinct innate responses can be elicited in immune and non-immune cells—including cardiomyocytes—using the same ligand-receptor system.

Suggested Citation

  • Yasunori Shintani & Hannes CA Drexler & Hidetaka Kioka & Cesare MN Terracciano & Steven R Coppen & Hiromi Imamura & Masaharu Akao & Junichi Nakai & Ann P Wheeler & Shuichiro Higo & Hiroyuki Nakayama &, 2014. "Toll-like receptor 9 protects non-immune cells from stress by modulating mitochondrial ATP synthesis through the inhibition of SERCA2," Nature, Nature, vol. 15(4), pages 438-445, April.
    • Handle: RePEc:nat:nature:v:15:y:2014:i:4:d:10.1002_embr.201337945
    DOI: 10.1002/embr.201337945
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    References listed on IDEAS

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    1. You-Me Kim & Melanie M. Brinkmann & Marie-Eve Paquet & Hidde L. Ploegh, 2008. "UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes," Nature, Nature, vol. 452(7184), pages 234-238, March.
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    More about this item

    Keywords

    danger signal; DNA; SERCA2; TLR9;
    All these keywords.

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