Ubr1-KO Mouse

Ubr1, or ubiquitin protein ligase E3 component n-recognin 1, is an E3 ubiquitin ligase that plays a crucial role in the proteolytic N-end rule pathway [4]. It binds to unstable N-terminal residues of substrate proteins and contributes to the formation of substrate-linked polyubiquitin chains, thus regulating protein degradation and turnover, which is vital for numerous cellular processes [3].

In various disease models, Ubr1 has been shown to have significant impacts. In anaplastic thyroid carcinoma (ATC) cells, Ubr1 deficiency reduced cell proliferation and migration in vitro and suppressed ATC cell growth in vivo. Ubr1 directly interacted with YAP, a critical effector of the Hippo pathway, promoted its monoubiquitylation, and stabilized it, thereby promoting ATC tumorigenesis [1]. In hypertensive male mice, in vivo silencing of Ubr1 using small interference RNA restored ACE2 levels, and intracerebroventricular infusion transiently decreased blood pressure. Ubr1 is a novel ubiquitin ligase targeting ACE2 in hypertension, and it may work synergistically with Nedd4-2 to ubiquitinate ACE2 [2,5]. In gastric cancer, knockdown of Ubr1 inhibited the proliferation, migration, and invasion of STAD cells and promoted apoptosis. Ubr1 overexpression was associated with poor prognostic outcomes and was correlated with immune cell infiltration and immunotherapeutic responses [3].

In conclusion, Ubr1 is essential for protein degradation regulation through the N-end rule pathway. Studies using gene-knockout models in mice have revealed its significance in diseases such as anaplastic thyroid carcinoma, hypertension, and gastric cancer. These findings provide potential therapeutic targets for these diseases, highlighting the importance of Ubr1 in understanding disease mechanisms and developing treatment strategies.

References:

1. Xia, Min, Liang, Chen, Yuan, Yu, Gong, Yan, Xie, Conghua. 2024. UBR1 promotes anaplastic thyroid carcinoma progression via stabilizing YAP through monoubiquitylation. In Scientific reports, 14, 19496. doi:10.1038/s41598-024-70458-8. https://pubmed.ncbi.nlm.nih.gov/39174635/

2. Elgazzaz, Mona, Lakkappa, Navya, Berdasco, Clara, Filipeanu, Catalin M, Lazartigues, Eric. 2024. UBR1 Promotes Sex-Dependent ACE2 Ubiquitination in Hypertension. In medRxiv : the preprint server for health sciences, , . doi:10.1101/2024.05.23.24307722. https://pubmed.ncbi.nlm.nih.gov/38826318/

3. Yuan, Weiwei, Han, Jianye, Chen, Chen, Xu, Aman, Sun, Minzhi. 2024. UBR1 is a prognostic biomarker and therapeutic target associated with immune cell infiltration in gastric cancer. In Aging, 16, 12029-12049. doi:10.18632/aging.206079. https://pubmed.ncbi.nlm.nih.gov/39181686/

4. Sukalo, Maja, Fiedler, Ariane, Guzmán, Celina, Witt, Heiko, Zenker, Martin. 2014. Mutations in the human UBR1 gene and the associated phenotypic spectrum. In Human mutation, 35, 521-31. doi:10.1002/humu.22538. https://pubmed.ncbi.nlm.nih.gov/24599544/

5. Elgazzaz, Mona, Lakkappa, Navya, Berdasco, Clara, Filipeanu, Catalin M, Lazartigues, Eric. 2024. UBR1 Promotes Sex-Dependent ACE2 Ubiquitination in Hypertension. In Hypertension (Dallas, Tex. : 1979), 82, 84-95. doi:10.1161/HYPERTENSIONAHA.124.23196. https://pubmed.ncbi.nlm.nih.gov/39601126/