Rnf5, also known as Ring-finger protein 5, is an E3 ubiquitin ligase. It is involved in various physiological processes such as protein localization, and plays a role in pathways related to endoplasmic reticulum stress, inflammation, and innate immunity [2,4,5]. Its biological importance extends to multiple disease-related processes, making it a potential target for therapeutic intervention. Genetic models, like gene knockout (KO) and conditional knockout (CKO) mouse models, can be valuable in studying its function.

In terms of specific findings, in SARS-CoV-2 research, Rnf5 interacts with and catalyzes the ubiquitination of the viral envelope protein on the 63rd lysine, leading to its degradation by the ubiquitin-proteasome system, thus restricting viral replication. The Rnf5 pharmacological activator Analog-1 alleviates disease development in a mouse infection model [1]. In acute myeloid leukemia (AML), increased Rnf5 abundance contributes to AML development and survival. Rnf5 inhibition decreases AML cell growth in culture, in patient-derived xenograft samples and in vivo, and delays MLL-AF9-driven leukemogenesis in mice [3]. In pathological cardiac hypertrophy, Rnf5 deficiency exacerbates cardiac hypertrophy, while overexpression has the opposite effect, as Rnf5 inhibits cardiac hypertrophy by promoting STING degradation through K48-linked polyubiquitination [4]. In hepatic ischemia-reperfusion (HIR) injury, Rnf5 knockdown in mice and hepatocytes increases inflammation and apoptosis, while overexpression has the opposite effect. Rnf5 interacts with phosphoglycerate mutase family member 5 (PGAM5) and mediates its degradation through K48-linked ubiquitination, suppressing the inflammatory response and cell apoptosis in HIR [5].

In conclusion, Rnf5, as an E3 ubiquitin ligase, has diverse functions in various biological processes and disease conditions. KO/CKO mouse models have been instrumental in revealing its roles in diseases such as SARS-CoV-2 infection, AML, pathological cardiac hypertrophy, and HIR injury. These findings provide insights into potential therapeutic strategies targeting Rnf5 for treating related diseases.

References:

1. Li, Zhaolong, Hao, Pengfei, Zhao, Zhilei, Li, Chang, Zhang, Wenyan. 2023. The E3 ligase RNF5 restricts SARS-CoV-2 replication by targeting its envelope protein for degradation. In Signal transduction and targeted therapy, 8, 53. doi:10.1038/s41392-023-01335-5. https://pubmed.ncbi.nlm.nih.gov/36737599/

2. Ge, Junyi, Zhang, Leiliang. 2024. RNF5: inhibiting antiviral immunity and shaping virus life cycle. In Frontiers in immunology, 14, 1324516. doi:10.3389/fimmu.2023.1324516. https://pubmed.ncbi.nlm.nih.gov/38250078/

3. Khateb, Ali, Deshpande, Anagha, Feng, Yongmei, Deshpande, Aniruddha J, Ronai, Ze'ev A. 2021. The ubiquitin ligase RNF5 determines acute myeloid leukemia growth and susceptibility to histone deacetylase inhibitors. In Nature communications, 12, 5397. doi:10.1038/s41467-021-25664-7. https://pubmed.ncbi.nlm.nih.gov/34518534/

4. Yang, Lu-Lu, Xiao, Wen-Chang, Li, Huan, Huang, Zhen, Zhang, Yan-Zhou. 2022. E3 ubiquitin ligase RNF5 attenuates pathological cardiac hypertrophy through STING. In Cell death & disease, 13, 889. doi:10.1038/s41419-022-05231-8. https://pubmed.ncbi.nlm.nih.gov/36270989/

5. Ding, Ming-Jie, Fang, Hao-Ran, Zhang, Jia-Kai, Zhang, Xiao-Jing, Guo, Wen-Zhi. 2022. E3 ubiquitin ligase ring finger protein 5 protects against hepatic ischemia reperfusion injury by mediating phosphoglycerate mutase family member 5 ubiquitination. In Hepatology (Baltimore, Md.), 76, 94-111. doi:10.1002/hep.32226. https://pubmed.ncbi.nlm.nih.gov/34735734/