Otud3, an ovarian-tumor-domain-containing deubiquitinase, is crucial in regulating protein homeostasis by blocking ubiquitin-dependent protein degradation. It is involved in diverse signaling pathways, including those related to immunity, inflammation, metabolism, and cell-cycle regulation [2,3].

Otud3 -/- mice challenged with a high-fat diet developed worse obesity, dyslipidemia, and insulin resistance compared to wild-type mice. This indicates that Otud3 is an important regulator of energy metabolism, with a rare c.863G > A mutation reducing its stability and catalytic activity and being associated with obesity and a higher diabetes risk [1]. In cancer, its role varies. For instance, in breast cancer, deletion of Otud3 in mice promotes tumor development, while in KrasG12D-driven lung adenocarcinoma, in vivo deletion of Otud3 slows down tumor initiation and progression [4]. Also, in liver cancer, Otud3 deficiency in mice leads to enhanced integrated stress response and accelerated tumor progression [5].

In conclusion, Otud3 is a key deubiquitinase with diverse functions. Its role in metabolism is evident from the phenotypes of gene-knockout mouse models in metabolic diseases. In cancer, the use of KO mouse models has shown its context-dependent role as either a tumor suppressor or an oncogene. These findings enhance our understanding of biological processes and disease mechanisms related to Otud3, potentially guiding future therapeutic strategies.

References:

1. Zhou, Na, Qi, Hailong, Liu, Junjun, Song, Yongfeng, Yin, Yuxin. 2022. Deubiquitinase OTUD3 regulates metabolism homeostasis in response to nutritional stresses. In Cell metabolism, 34, 1023-1041.e8. doi:10.1016/j.cmet.2022.05.005. https://pubmed.ncbi.nlm.nih.gov/35675826/

2. Xu, Qiao, He, Lan, Zhang, Shubing, Di, Xiaotang, Jiang, Hao. 2023. Deubiquitinase OTUD3: a double-edged sword in immunity and disease. In Frontiers in cell and developmental biology, 11, 1237530. doi:10.3389/fcell.2023.1237530. https://pubmed.ncbi.nlm.nih.gov/37829187/

3. Hou, Dan, Yu, Dan, Yang, Guoshuai, Hu, Yujie, Li, Hongxin. . Research progress in deubiquitinase OTUD3. In Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences, 49, 1341-1352. doi:10.11817/j.issn.1672-7347.2024.230581. https://pubmed.ncbi.nlm.nih.gov/39788523/

4. Du, Tongde, Li, Hongchang, Fan, Yongsheng, Han, Chuanchun, Zhang, Lingqiang. 2019. The deubiquitylase OTUD3 stabilizes GRP78 and promotes lung tumorigenesis. In Nature communications, 10, 2914. doi:10.1038/s41467-019-10824-7. https://pubmed.ncbi.nlm.nih.gov/31266968/

5. Dai, Hongmiao, Wu, Bo, Ge, Yingwei, Li, Hongchang, Zhang, Lingqiang. 2024. Deubiquitylase OTUD3 regulates integrated stress response to suppress progression and sorafenib resistance of liver cancer. In Cell reports, 43, 114487. doi:10.1016/j.celrep.2024.114487. https://pubmed.ncbi.nlm.nih.gov/38996071/