Otub1-KO Mouse

Otub1, short for ovarian tumor domain-containing ubiquitin aldehyde-binding protein 1, is a crucial deubiquitinase within the OTU superfamily. It plays a significant role in multiple physiological processes, such as DNA damage repair, cytokines secretion, and regulating the stability of various proteins [4]. It is involved in pathways related to immune response, ferroptosis, and cell metabolism, and is of great biological importance in maintaining normal cellular functions. Genetic models, like gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying its functions.

Global and conditional osteoblast KO of Otub1 result in low bone mass and poor bone strength due to osteogenic differentiation and mineralization defects. Mechanistically, OTUB1 stabilizes FGFR2, a key osteogenesis regulator, by inhibiting SMURF1-mediated FGFR2 ubiquitination. AAV9-delivered FGFR2 rescued bone mass loss in osteoblast-specific Otub1-deleted mice, and restoring OTUB1 levels in osteoporotic mice alleviated osteopenia [1]. In gastric cancer, CST1 promotes metastasis by recruiting OTUB1 to relieve GPX4 ubiquitination, improving its stability and inhibiting ferroptosis [2]. In breast cancer, OTUB1 deubiquitinates MYC at K323, blocking its degradation, promoting HK2-mediated glycolysis, and tumorigenesis [3].

In conclusion, Otub1, through its deubiquitinase activity, plays essential roles in maintaining protein stability and regulating various biological processes. Studies using KO/CKO mouse models have revealed its significance in diseases like osteoporosis, gastric cancer, and breast cancer, providing potential therapeutic targets for these conditions.

References:

1. Zhu, Qiong, Fu, Yesheng, Cui, Chun-Ping, Liu, Cui Hua, Zhang, Lingqiang. 2023. OTUB1 promotes osteoblastic bone formation through stabilizing FGFR2. In Signal transduction and targeted therapy, 8, 142. doi:10.1038/s41392-023-01354-2. https://pubmed.ncbi.nlm.nih.gov/37024477/

2. Li, Dongbao, Wang, Yuhong, Dong, Chao, Hu, Lin, Zhou, Jin. 2022. CST1 inhibits ferroptosis and promotes gastric cancer metastasis by regulating GPX4 protein stability via OTUB1. In Oncogene, 42, 83-98. doi:10.1038/s41388-022-02537-x. https://pubmed.ncbi.nlm.nih.gov/36369321/

3. Han, Xue, Ren, Chune, Lu, Chao, Yang, Tingting, Yu, Zhenhai. 2022. Deubiquitination of MYC by OTUB1 contributes to HK2 mediated glycolysis and breast tumorigenesis. In Cell death and differentiation, 29, 1864-1873. doi:10.1038/s41418-022-00971-8. https://pubmed.ncbi.nlm.nih.gov/35296795/

4. Liao, Yihao, Yang, Mengyue, Wang, Keke, Zhong, Boqiang, Jiang, Ning. 2021. Deubiquitinating enzyme OTUB1 in immunity and cancer: Good player or bad actor? In Cancer letters, 526, 248-258. doi:10.1016/j.canlet.2021.12.002. https://pubmed.ncbi.nlm.nih.gov/34875341/