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Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation

Author

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  • Meihua Jin

    (Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University)

  • Hiroki Shiwaku

    (Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University)

  • Hikari Tanaka

    (Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University)

  • Takayuki Obita

    (University of Toyama, 2630 Sugitani)

  • Sakurako Ohuchi

    (University of Toyama, 2630 Sugitani)

  • Yuki Yoshioka

    (Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University)

  • Xiaocen Jin

    (Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University)

  • Kanoh Kondo

    (Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University)

  • Kyota Fujita

    (Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University)

  • Hidenori Homma

    (Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University)

  • Kazuyuki Nakajima

    (Institute of Bioinformatics, Soka University)

  • Mineyuki Mizuguchi

    (University of Toyama, 2630 Sugitani)

  • Hitoshi Okazawa

    (Medical Research Institute and Center for Brain Integration Research, Tokyo Medical and Dental University)

Abstract

Brain inflammation generally accompanies and accelerates neurodegeneration. Here we report a microglial mechanism in which polyglutamine binding protein 1 (PQBP1) senses extrinsic tau 3R/4R proteins by direct interaction and triggers an innate immune response by activating a cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING) pathway. Tamoxifen-inducible and microglia-specific depletion of PQBP1 in primary culture in vitro and mouse brain in vivo shows that PQBP1 is essential for sensing-tau to induce nuclear translocation of nuclear factor κB (NFκB), NFκB-dependent transcription of inflammation genes, brain inflammation in vivo, and eventually mouse cognitive impairment. Collectively, PQBP1 is an intracellular receptor in the cGAS-STING pathway not only for cDNA of human immunodeficiency virus (HIV) but also for the transmissible neurodegenerative disease protein tau. This study characterises a mechanism of brain inflammation that is common to virus infection and neurodegenerative disorders.

Suggested Citation

  • Meihua Jin & Hiroki Shiwaku & Hikari Tanaka & Takayuki Obita & Sakurako Ohuchi & Yuki Yoshioka & Xiaocen Jin & Kanoh Kondo & Kyota Fujita & Hidenori Homma & Kazuyuki Nakajima & Mineyuki Mizuguchi & Hi, 2021. "Tau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation," Nature Communications, Nature, vol. 12(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26851-2
    DOI: 10.1038/s41467-021-26851-2
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    1. Xiaocen Jin & Hikari Tanaka & Meihua Jin & Kyota Fujita & Hidenori Homma & Maiko Inotsume & Huang Yong & Kenichi Umeda & Noriyuki Kodera & Toshio Ando & Hitoshi Okazawa, 2023. "PQBP5/NOL10 maintains and anchors the nucleolus under physiological and osmotic stress conditions," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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