Uba7, also known as UBE1L, is a specific E1-like ubiquitin-activating enzyme crucial for the activation of ISG15, a ubiquitin-like protein [1,2,5]. The ISG15-Uba7 system is part of the innate immune response pathway, with ISG15 playing roles in antiviral activity, regulation of signal transduction, apoptosis, and autophagy [2]. Genetic models can be valuable for studying Uba7 as they can help reveal its in-vivo functions.

Phylogenetic comparisons suggest Uba7 descended from gene duplication and it exhibits ubiquitin-activation activity in fish but not tetrapods, indicating an evolving specificity in the ISG15/Uba7 relationship [1]. Inhibition of Uba7 expression via shRNA in neuroblastoma and microglial cell lines increased rabies virus (RABV) titers, and in mouse brains, it also increased RABV titers and decreased mouse survivorship, showing that Uba7 inhibits RABV replication in vitro and in vivo [3]. In myelodysplastic neoplasm with SF3B1 mutations, aberrant alternative splicing of Uba7 leads to reduced gene expression, and low Uba7 gene expression is associated with poor overall survival in chronic lymphocytic leukemia and multiple tumor types in the TCGA database [4]. In breast cancer, Uba7 expression is decreased, associated with clinical characteristics and prognosis, making it a potential biomarker and treatment target [6]. In fallopian tube epithelial cells, disruption of Uba7 expression attenuated the activation of IRF3 by RIGI or MDA5 and affected NFκB activation, indicating that Uba7-mediated ISGylation enhances dsRNA-induced interferon response and NFκB signaling [7]. In HepG2 cells, furosine induced apoptosis and activated the expression of Uba7, which significantly affected downstream apoptosis factors [8]. However, in K-rasLA2 mice, Ube1l (Uba7) deficiency did not accelerate lung cancer development, suggesting it may not be a tumor suppressor gene in this model [9].

In conclusion, Uba7 is essential for activating ISG15 and plays a role in the innate immune response. Studies using gene-knockdown or knockout models have revealed its significance in various disease conditions such as viral infections, hematological malignancies, breast cancer, and apoptosis-related processes. Although its role as a tumor suppressor gene remains unclear in some models, further research could provide more insights into its functions in disease development and potentially lead to new treatment strategies.

References:

1. Liu, Shengyin, Hu, Guangxu, Luo, Shuhui, Huang, Honghui, Li, Hongtao. 2022. Insights into the evolution of the ISG15 and UBA7 system. In Genomics, 114, 110302. doi:10.1016/j.ygeno.2022.110302. https://pubmed.ncbi.nlm.nih.gov/35134494/

2. Afsar, Mohammad, Liu, GuanQun, Jia, Lijia, Gack, Michaela U, Olsen, Shaun K. 2023. Cryo-EM structures of Uba7 reveal the molecular basis for ISG15 activation and E1-E2 thioester transfer. In Nature communications, 14, 4786. doi:10.1038/s41467-023-39780-z. https://pubmed.ncbi.nlm.nih.gov/37553340/

3. Zhao, Pingsen, Jiang, Tianqi, Zhong, Zhixiong, Yang, Songtao, Xia, Xianzhu. 2017. Inhibition of rabies virus replication by interferon-stimulated gene 15 and its activating enzyme UBA7. In Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases, 56, 44-53. doi:10.1016/j.meegid.2017.10.016. https://pubmed.ncbi.nlm.nih.gov/29056542/

4. Alatawi, Sael, Alzahrani, Othman R, Alatawi, Fuad A, Almotiri, Alhomidi, Almsned, Fahad M. 2025. Identification of UBA7 expression downregulation in myelodysplastic neoplasm with SF3B1 mutations. In Scientific reports, 15, 10856. doi:10.1038/s41598-025-95738-9. https://pubmed.ncbi.nlm.nih.gov/40158006/

5. Wallace, Iona, Baek, Kheewoong, Prabu, J Rajan, Schulman, Brenda A, Swatek, Kirby N. 2023. Insights into the ISG15 transfer cascade by the UBE1L activating enzyme. In Nature communications, 14, 7970. doi:10.1038/s41467-023-43711-3. https://pubmed.ncbi.nlm.nih.gov/38042859/

6. Lin, Meng, Li, Yanqing, Qin, Shanshan, Jiao, Yan, Hua, Fang. 2020. Ubiquitin-like modifier-activating enzyme 7 as a marker for the diagnosis and prognosis of breast cancer. In Oncology letters, 19, 2773-2784. doi:10.3892/ol.2020.11406. https://pubmed.ncbi.nlm.nih.gov/32218830/

7. Madaan, Vidushi, Kollara, Alexandra, Spaner, David, Brown, Theodore J. 2024. ISGylation enhances dsRNA-induced interferon response and NFκB signaling in fallopian tube epithelial cells. In The Journal of biological chemistry, 300, 107686. doi:10.1016/j.jbc.2024.107686. https://pubmed.ncbi.nlm.nih.gov/39159817/

8. Li, Huiying, Xing, Lei, Zhao, Nan, Wang, Jiaqi, Zheng, Nan. 2018. Furosine Induced Apoptosis by the Regulation of STAT1/STAT2 and UBA7/UBE2L6 Genes in HepG2 Cells. In International journal of molecular sciences, 19, . doi:10.3390/ijms19061629. https://pubmed.ncbi.nlm.nih.gov/29857509/

9. Yin, Xiaoyan, Cong, Xiuli, Yan, Ming, Zhang, Dong-Er. 2008. Deficiency of a potential 3p21.3 tumor suppressor gene UBE1L (UBA7) does not accelerate lung cancer development in K-rasLA2 mice. In Lung cancer (Amsterdam, Netherlands), 63, 194-200. doi:10.1016/j.lungcan.2008.05.009. https://pubmed.ncbi.nlm.nih.gov/18571763/