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

• Published in: Nature communications 2022-10, Vol.13 (1), p.5973-19, Article 5973
• Main Authors: Xiong, Tian-Chen, Wei, Ming-Cong, Li, Fang-Xu, Shi, Miao, Gan, Hu, Tang, Zhen, Dong, Hong-Peng, Liuyu, Tianzi, Gao, Pu, Zhong, Bo, Zhang, Zhi-Dong, Lin, Dandan
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 13/31; 14; 14/63; 631/250/256; 631/250/262; 631/250/262/2106; 631/250/38; 64; 64/60; 82/80; 96; 96/95; Animals; Autoimmunity; Cytokines; Deoxyribonucleic acid; DNA; Gene expression; Herpes simplex; Herpes Simplex - immunology; Herpes viruses; Herpesvirus 1, Human; Humanities and Social Sciences; Immunity; Immunity, Innate; Inflammation; Interferon; Interferon Type I; Lethality; Mice; multidisciplinary; Myeloid cells; Nucleotidyltransferases - metabolism; Oligomerization; Phenotypes; Post-translation; Science; Science (multidisciplinary); Stability; Tamoxifen; Translation; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-33671-5

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; Arih1 fl/fl mice and Lyz2 -Cre; Arih1 fl/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. The activity and stability of the cytosolic DNA sensor cGAS, a key mediator of innate antiviral immunity and autoimmunity, is fine-tuned by post-translational modifications. Here, the authors demonstrate that the ubiquitin E3 ligase ARIH1 catalyzes the mono-ISGylation of cGAS and promotes its oligomerization in response to viral and self DNA.