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The E3 ubiquitin ligase ARIH1 promotes antiviral immunity and autoimmunity by inducing mono-ISGylation and oligomerization of cGAS

Author

Listed:
  • Tian-Chen Xiong

    (Wuhan University
    Chongqing International Institute for Immunology
    Wuhan University
    Chinese Academy of Medical Sciences)

  • Ming-Cong Wei

    (Wuhan University
    Wuhan University)

  • Fang-Xu Li

    (Wuhan University
    Wuhan University)

  • Miao Shi

    (Chinese Academy of Sciences)

  • Hu Gan

    (Wuhan University
    Wuhan University
    Wuhan University)

  • Zhen Tang

    (Wuhan University
    Wuhan University
    Wuhan University)

  • Hong-Peng Dong

    (Wuhan University
    Wuhan University)

  • Tianzi Liuyu

    (Wuhan University
    Wuhan University)

  • Pu Gao

    (Chinese Academy of Sciences)

  • Bo Zhong

    (Wuhan University
    Wuhan University
    Chinese Academy of Medical Sciences
    Wuhan University)

  • Zhi-Dong Zhang

    (Wuhan University)

  • Dandan Lin

    (Renmin Hospital of Wuhan University)

Abstract

The cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) plays a critical role in antiviral immunity and autoimmunity. The activity and stability of cGAS are fine-tuned by post-translational modifications. Here, we show that ariadne RBR E3 ubiquitin protein ligase 1 (ARIH1) catalyzes the mono-ISGylation and induces the oligomerization of cGAS, thereby promoting antiviral immunity and autoimmunity. Knockdown or knockout of ARIH1 significantly inhibits herpes simplex virus 1 (HSV-1)- or cytoplasmic DNA-induced expression of type I interferons (IFNs) and proinflammatory cytokines. Consistently, tamoxifen-treated ER-Cre;Arih1fl/fl mice and Lyz2-Cre; Arih1fl/fl mice are hypersensitive to HSV-1 infection compared with the controls. In addition, deletion of ARIH1 in myeloid cells alleviates the autoimmune phenotypes and completely rescues the autoimmune lethality caused by TREX1 deficiency. Mechanistically, HSV-1- or cytosolic DNA-induced oligomerization and activation of cGAS are potentiated by ISGylation at its K187 residue, which is catalyzed by ARIH1. Our findings thus reveal an important role of ARIH1 in innate antiviral and autoimmune responses and provide insight into the post-translational regulation of cGAS.

Suggested Citation

  • Tian-Chen Xiong & Ming-Cong Wei & Fang-Xu Li & Miao Shi & Hu Gan & Zhen Tang & Hong-Peng Dong & Tianzi Liuyu & Pu Gao & Bo Zhong & Zhi-Dong Zhang & Dandan Lin, 2022. "The E3 ubiquitin ligase ARIH1 promotes antiviral immunity and autoimmunity by inducing mono-ISGylation and oligomerization of cGAS," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33671-5
    DOI: 10.1038/s41467-022-33671-5
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    1. Xiaolan Liu & Xufeng Cen & Ronghai Wu & Ziyan Chen & Yanqi Xie & Fengqi Wang & Bing Shan & Linghui Zeng & Jichun Zhou & Bojian Xie & Yangjun Cai & Jinyan Huang & Yingjiqiong Liang & Youqian Wu & Chao , 2023. "ARIH1 activates STING-mediated T-cell activation and sensitizes tumors to immune checkpoint blockade," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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