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ZCCHC3 is a co-sensor of cGAS for dsDNA recognition in innate immune response

Author

Listed:
  • Huan Lian

    (Wuhan University)

  • Jin Wei

    (Wuhan University)

  • Ru Zang

    (Wuhan University)

  • Wen Ye

    (Wuhan University)

  • Qing Yang

    (Wuhan University)

  • Xia-Nan Zhang

    (Wuhan University
    College of Life Sciences Wuhan University)

  • Yun-Da Chen

    (Wuhan University
    College of Life Sciences Wuhan University)

  • Yu-Zhi Fu

    (Chinese Academy of Sciences)

  • Ming-Ming Hu

    (Wuhan University)

  • Cao-Qi Lei

    (Wuhan University
    College of Life Sciences Wuhan University)

  • Wei-Wei Luo

    (Chinese Academy of Sciences)

  • Shu Li

    (Wuhan University)

  • Hong-Bing Shu

    (Wuhan University
    College of Life Sciences Wuhan University)

Abstract

Cyclic GMP-AMP synthase (cGAS) senses double-strand (ds) DNA in the cytosol and then catalyzes synthesis of the second messenger cGAMP, which activates the adaptor MITA/STING to initiate innate antiviral response. How cGAS activity is regulated remains enigmatic. Here, we identify ZCCHC3, a CCHC-type zinc-finger protein, as a positive regulator of cytosolic dsDNA- and DNA virus-triggered signaling. We show that ZCCHC3-deficiency inhibits dsDNA- and DNA virus-triggered induction of downstream effector genes, and that ZCCHC3-deficient mice are more susceptible to lethal herpes simplex virus type 1 or vaccinia virus infection. ZCCHC3 directly binds to dsDNA, enhances the binding of cGAS to dsDNA, and is important for cGAS activation following viral infection. Our results suggest that ZCCHC3 is a co-sensor for recognition of dsDNA by cGAS, which is important for efficient innate immune response to cytosolic dsDNA and DNA virus.

Suggested Citation

  • Huan Lian & Jin Wei & Ru Zang & Wen Ye & Qing Yang & Xia-Nan Zhang & Yun-Da Chen & Yu-Zhi Fu & Ming-Ming Hu & Cao-Qi Lei & Wei-Wei Luo & Shu Li & Hong-Bing Shu, 2018. "ZCCHC3 is a co-sensor of cGAS for dsDNA recognition in innate immune response," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05559-w
    DOI: 10.1038/s41467-018-05559-w
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    Cited by:

    1. Beibei Fu & Yan Xiong & Zhou Sha & Weiwei Xue & Binbin Xu & Shun Tan & Dong Guo & Feng Lin & Lulu Wang & Jianjian Ji & Yang Luo & Xiaoyuan Lin & Haibo Wu, 2023. "SEPTIN2 suppresses an IFN-γ-independent, proinflammatory macrophage activation pathway," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Zehua Shang & Sitao Zhang & Jinrui Wang & Lili Zhou & Xinyue Zhang & Daniel D. Billadeau & Peiguo Yang & Lingqiang Zhang & Fangfang Zhou & Peng Bai & Da Jia, 2024. "TRIM25 predominately associates with anti-viral stress granules," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Maja Olecka & Alena Bömmel & Lena Best & Madlen Haase & Silke Foerste & Konstantin Riege & Thomas Dost & Stefano Flor & Otto W. Witte & Sören Franzenburg & Marco Groth & Björn Eyss & Christoph Kaleta , 2024. "Nonlinear DNA methylation trajectories in aging male mice," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. 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.

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