Rnf115, also known as breast cancer-associated gene 2 (BCA2), is an E3 ubiquitin ligase. It is involved in multiple biological processes, regulating immune responses, autophagy, and cancer-related pathways [1,2,3,4,5,6,7,8,9,10]. Ubiquitination, a key function of Rnf115, impacts the stability and function of target proteins, influencing various cellular activities.

In gene knockout studies, Rnf115 deletion protected mice from acute liver injury by promoting autophagy and inhibiting the inflammatory response [1]. Rnf115 -/- livers showed increased autophagy, removing damaged mitochondria and reducing hepatocyte apoptosis. Additionally, Rnf115 inactivation inhibited M1-type macrophage activation. In Trex1 -/- mice and STINGN153S/WT bone marrow chimeric mice, knockout of Rnf115 alleviated STING-mediated inflammation and autoimmunity [2]. In Rnf115 -/- mice, there was also altered sensitivity to viral infections; they were hypo-sensitive to EMCV and hyper-sensitive to HSV-1 due to Rnf115's dual-role in ubiquitinating MAVS and MITA [4]. Rnf115 -/- mice also showed enhanced phagosomal maturation and reduced tissue damage in response to S. aureus infection [9]. In contrast, in cancer-related studies, overexpression of Rnf115 in thyroid carcinoma, lung adenocarcinoma, and gastric cancer promoted tumor progression [5,7,6].

In conclusion, Rnf115 is a crucial E3 ubiquitin ligase involved in immune regulation, autophagy, and cancer development. Gene knockout mouse models have significantly contributed to understanding its role in acute liver injury, autoimmune diseases, viral infections, bacterial infections, and cancer. These findings provide potential therapeutic targets for related diseases.

References:

1. Feng, Jinqiu, Ye, Shufang, Hai, Bao, Lu, Wenping, Chen, Yingyu. 2023. RNF115/BCA2 deficiency alleviated acute liver injury in mice by promoting autophagy and inhibiting inflammatory response. In Cell death & disease, 14, 855. doi:10.1038/s41419-023-06379-7. https://pubmed.ncbi.nlm.nih.gov/38129372/

2. Zhang, Zhi-Dong, Shi, Chang-Rui, Li, Fang-Xu, Zhong, Bo, Lin, Dandan. 2024. Disulfiram ameliorates STING/MITA-dependent inflammation and autoimmunity by targeting RNF115. In Cellular & molecular immunology, 21, 275-291. doi:10.1038/s41423-024-01131-3. https://pubmed.ncbi.nlm.nih.gov/38267694/

3. Zhang, Zhi-Dong, Li, Hong-Xu, Gan, Hu, Zhong, Bo, Lin, Dandan. 2022. RNF115 Inhibits the Post-ER Trafficking of TLRs and TLRs-Mediated Immune Responses by Catalyzing K11-Linked Ubiquitination of RAB1A and RAB13. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 9, e2105391. doi:10.1002/advs.202105391. https://pubmed.ncbi.nlm.nih.gov/35343654/

4. Zhang, Zhi-Dong, Xiong, Tian-Chen, Yao, Shu-Qi, Lin, Dandan, Zhong, Bo. 2020. RNF115 plays dual roles in innate antiviral responses by catalyzing distinct ubiquitination of MAVS and MITA. In Nature communications, 11, 5536. doi:10.1038/s41467-020-19318-3. https://pubmed.ncbi.nlm.nih.gov/33139700/

5. Zhu, Jinxiang, Guo, Longwei, Dai, Hao, Zhao, Qian, Xu, Chongwen. 2024. RNF115 aggravates tumor progression through regulation of CDK10 degradation in thyroid carcinoma. In Cell biology and toxicology, 40, 14. doi:10.1007/s10565-024-09845-w. https://pubmed.ncbi.nlm.nih.gov/38376606/

6. Li, Riyong, Gu, Zhaohui, Zhang, Xuan, Lv, Ping, Chen, Yingyu. 2020. RNF115 deletion inhibits autophagosome maturation and growth of gastric cancer. In Cell death & disease, 11, 810. doi:10.1038/s41419-020-03011-w. https://pubmed.ncbi.nlm.nih.gov/32980859/

7. Wu, Xiao-Ting, Wang, Yu-Han, Cai, Xiao-Yue, Lu, Wen-Feng, Zhang, Ming. 2021. RNF115 promotes lung adenocarcinoma through Wnt/β-catenin pathway activation by mediating APC ubiquitination. In Cancer & metabolism, 9, 7. doi:10.1186/s40170-021-00243-y. https://pubmed.ncbi.nlm.nih.gov/33509267/

8. Luo, Zhigang, Ye, Xin, Shou, Feng, Li, Fugang, Wang, Gang. 2020. RNF115-mediated ubiquitination of p53 regulates lung adenocarcinoma proliferation. In Biochemical and biophysical research communications, 530, 425-431. doi:10.1016/j.bbrc.2020.05.061. https://pubmed.ncbi.nlm.nih.gov/32553631/

9. Bilkei-Gorzo, Orsolya, Heunis, Tiaan, Marín-Rubio, José Luis, Härtlova, Anetta, Trost, Matthias. 2022. The E3 ubiquitin ligase RNF115 regulates phagosome maturation and host response to bacterial infection. In The EMBO journal, 41, e108970. doi:10.15252/embj.2021108970. https://pubmed.ncbi.nlm.nih.gov/36281581/

10. Gu, Zhaohui, Feng, Jinqiu, Ye, Shufang, Zhu, Bin, Chen, Yingyu. 2025. RNF115 deficiency upregulates autophagy and inhibits hepatocellular carcinoma growth. In Chinese medical journal, 138, 754-756. doi:10.1097/CM9.0000000000003466. https://pubmed.ncbi.nlm.nih.gov/39932173/