Ariadne RBR E3 ubiquitin-protein ligase 1 (ARIH1) is an E3 ubiquitin ligase that plays crucial roles in multiple biological pathways. It is involved in immune-related pathways, such as the STING pathway, and also impacts processes like protein degradation and cell-state transitions. By regulating ubiquitination, ARIH1 influences the stability and function of various proteins, which is of great biological importance in processes including immunity, tumor growth, and cell plasticity [1-3, 5, 9].

In terms of tumor-related research, in an ICB-insensitive tumor model, cisplatin upregulates ARIH1 expression, and ARIH1 overexpression promotes cytotoxic T-cell infiltration, inhibits tumor growth, and enhances the effect of PD-L1 blockade. ARIH1 mediates ubiquitination and degradation of DNA-PKcs to activate the STING pathway [1]. In another study, ARIH1 was identified as the E3 ubiquitin ligase responsible for targeting PD-L1 for proteasomal degradation, and its overexpression suppresses tumor growth and promotes cytotoxic T-cell activation in wild-type mice [2]. For antiviral immunity, knockdown or knockout of ARIH1 in mice significantly inhibits herpes simplex virus 1 (HSV-1)-or cytoplasmic DNA-induced expression of type I interferons (IFNs) and proinflammatory cytokines. Tamoxifen-treated ER-Cre;Arih1fl/fl mice and Lyz2-Cre; Arih1fl/fl mice are hypersensitive to HSV-1 infection compared with controls [3].

In conclusion, ARIH1 is a key E3 ubiquitin ligase involved in immune responses, both antiviral and anti-tumor. The use of gene knockout and conditional knockout mouse models has been instrumental in revealing its role in tumor immunity and antiviral immunity. Understanding ARIH1's functions provides potential strategies for improving cancer immunotherapy and combating viral infections.

References:

1. Liu, Xiaolan, Cen, Xufeng, Wu, Ronghai, Wang, Dongrui, Xia, Hongguang. 2023. ARIH1 activates STING-mediated T-cell activation and sensitizes tumors to immune checkpoint blockade. In Nature communications, 14, 4066. doi:10.1038/s41467-023-39920-5. https://pubmed.ncbi.nlm.nih.gov/37429863/

2. Wu, Youqian, Zhang, Chao, Liu, Xiaolan, Ying, Songmin, Xia, Hongguang. 2021. ARIH1 signaling promotes anti-tumor immunity by targeting PD-L1 for proteasomal degradation. In Nature communications, 12, 2346. doi:10.1038/s41467-021-22467-8. https://pubmed.ncbi.nlm.nih.gov/33879767/

3. Xiong, Tian-Chen, Wei, Ming-Cong, Li, Fang-Xu, Zhang, Zhi-Dong, Lin, Dandan. 2022. The E3 ubiquitin ligase ARIH1 promotes antiviral immunity and autoimmunity by inducing mono-ISGylation and oligomerization of cGAS. In Nature communications, 13, 5973. doi:10.1038/s41467-022-33671-5. https://pubmed.ncbi.nlm.nih.gov/36217001/