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

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 () and Dandan Lin ()
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Tian-Chen Xiong: Wuhan University
Ming-Cong Wei: Wuhan University
Fang-Xu Li: Wuhan University
Miao Shi: Chinese Academy of Sciences
Hu Gan: Wuhan University
Zhen Tang: Wuhan University
Hong-Peng Dong: Wuhan University
Tianzi Liuyu: Wuhan University
Pu Gao: Chinese Academy of Sciences
Bo Zhong: Wuhan University
Zhi-Dong Zhang: Wuhan University
Dandan Lin: Renmin Hospital of Wuhan University

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33671-5

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