2. Academic Validation
  3. The E3 ubiquitin ligase ARIH1 promotes antiviral immunity and autoimmunity by inducing mono-ISGylation and oligomerization of cGAS

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

  • Nat Commun. 2022 Oct 10;13(1):5973. doi: 10.1038/s41467-022-33671-5.
Tian-Chen Xiong # 1 2 3 4,  Ming-Cong Wei # 1 3,  Fang-Xu Li # 1 3,  Miao Shi 5,  Hu Gan 1 3 6,  Zhen Tang 1 3 6,  Hong-Peng Dong 1 3,  Tianzi Liuyu 1 3,  Pu Gao 5,  Bo Zhong 7 8 9 10,  Zhi-Dong Zhang 11,  Dandan Lin 12
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • 2 Chongqing International Institute for Immunology, Chongqing, China.
  • 3 TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.
  • 4 Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China.
  • 5 CAS Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 6 Department of Virology, College of Life Sciences, Wuhan University, Wuhan, China.
  • 7 Department of Gastrointestinal Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China. zhongbo@whu.edu.cn.
  • 8 TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China. zhongbo@whu.edu.cn.
  • 9 Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China. zhongbo@whu.edu.cn.
  • 10 Department of Virology, College of Life Sciences, Wuhan University, Wuhan, China. zhongbo@whu.edu.cn.
  • 11 Department of Gastrointestinal Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China. zhidongzhang@whu.edu.cn.
  • 12 Cancer Center, Renmin Hospital of Wuhan University, Wuhan, China. lindandan@whu.edu.cn.
  • # Contributed equally.
PMID: 36217001 DOI: 10.1038/s41467-022-33671-5
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.

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