Ubr7-KO Mouse

Ubr7, or Ubiquitin protein ligase E3 component N-recognin 7, is an E3 ubiquitin ligase. It plays diverse roles in various biological processes, with its functions related to the ubiquitin-proteasome system, which is crucial for intracellular protein turnover. It is involved in pathways such as glycolysis, immune response, and extracellular matrix remodeling, and is thus of great biological importance. Genetic models, like KO or CKO mouse models, can be valuable for studying its functions [1-9].

In HCC, Ubr7 loss promotes tumorigenesis both in vitro and in vivo. Ubr7 inhibits glycolysis by indirectly suppressing HK2 expression, a downstream target of Nrf2/Bach1 axis. It regulates H2BK120ub to bind to Keap1 promoter, modulating Keap1 expression and downstream Nrf2/Bach1/HK2 signaling [1]. In TNBC, Ubr7 loss leads to a reduction in H3K27me3, activating ECM genes and influencing matrix stiffness and invasiveness [2]. In HBV-induced HCC, Ubr7 promotes pathogenesis by ubiquitinating Sp110, downregulating genes in the type I interferon response pathway [3]. In PDAC, depletion of Ubr7 increases carcinogenesis and the immunosuppressive microenvironment by enhancing PRMT5-mediated glycolysis [4]. In T-ALL, Ubr7, as a transcriptional target of NOTCH1, stabilizes PRPS catalytic subunits, promoting nucleotide biosynthesis and cell proliferation [5]. In C. elegans, ubr-7 interacts with ubr-5 in the Notch signaling pathway, influencing development and embryo formation [6]. In triple-negative breast cancer, low Ubr7 expression is correlated with tumor occurrence and metastasis, and Ubr7 knockdown enhances invasiveness and epithelial-to-mesenchymal transition [7].

In conclusion, Ubr7 is a multifunctional E3 ubiquitin ligase. Model-based research, especially through KO/CKO mouse models, has revealed its significance in diseases like HCC, TNBC, HBV-induced HCC, PDAC, T-ALL, and in a neurodevelopmental syndrome. It is involved in key biological processes such as glycolysis, immune response, extracellular matrix remodeling, nucleotide biosynthesis, and Notch signaling, providing potential therapeutic targets for these disease areas.

References:

1. Zhao, Liang, Kang, Min, Liu, Xiaomeng, Chang, Antao, Tang, Bo. 2022. UBR7 inhibits HCC tumorigenesis by targeting Keap1/Nrf2/Bach1/HK2 and glycolysis. In Journal of experimental & clinical cancer research : CR, 41, 330. doi:10.1186/s13046-022-02528-6. https://pubmed.ncbi.nlm.nih.gov/36419136/

2. Adhikari, Swagata, Singh, Vipin, Nandi, Sandhik, Notani, Dimple, Das, Chandrima. 2024. UBR7 in concert with EZH2 inhibits the TGF-β signaling leading to extracellular matrix remodeling. In Cell reports, 43, 114394. doi:10.1016/j.celrep.2024.114394. https://pubmed.ncbi.nlm.nih.gov/38923455/

3. Singh, Vipin, Mondal, Atanu, Adhikary, Santanu, Roy, Siddhartha, Das, Chandrima. 2024. UBR7 E3 Ligase Suppresses Interferon-β Mediated Immune Signaling by Targeting Sp110 in Hepatitis B Virus-Induced Hepatocellular Carcinoma. In ACS infectious diseases, 10, 3775-3796. doi:10.1021/acsinfecdis.4c00213. https://pubmed.ncbi.nlm.nih.gov/38938101/

4. Feng, Maoxiao, Jiao, Qinlian, Ren, Yidan, Zhao, Miaoqing, Bi, Lei. 2024. The interaction between UBR7 and PRMT5 drives PDAC resistance to gemcitabine by regulating glycolysis and immune microenvironment. In Cell death & disease, 15, 758. doi:10.1038/s41419-024-07145-z. https://pubmed.ncbi.nlm.nih.gov/39424627/

5. Srivastava, Shashank, Sahu, Umakant, Zhou, Yalu, Ben-Sahra, Issam, Foltz, Daniel R. 2021. NOTCH1-driven UBR7 stimulates nucleotide biosynthesis to promote T cell acute lymphoblastic leukemia. In Science advances, 7, . doi:10.1126/sciadv.abc9781. https://pubmed.ncbi.nlm.nih.gov/33571115/

6. Li, Chunmei, Beauregard-Lacroix, Eliane, Kondratev, Christine, Leroux, Michel R, Campeau, Philippe M. 2020. UBR7 functions with UBR5 in the Notch signaling pathway and is involved in a neurodevelopmental syndrome with epilepsy, ptosis, and hypothyroidism. In American journal of human genetics, 108, 134-147. doi:10.1016/j.ajhg.2020.11.018. https://pubmed.ncbi.nlm.nih.gov/33340455/

7. Adhikary, Santanu, Chakravarti, Deepavali, Terranova, Christopher, Rai, Kunal, Das, Chandrima. 2019. Atypical plant homeodomain of UBR7 functions as an H2BK120Ub ligase and breast tumor suppressor. In Nature communications, 10, 1398. doi:10.1038/s41467-019-08986-5. https://pubmed.ncbi.nlm.nih.gov/30923315/