Otud1, an ovarian tumor protease (OTU) family deubiquitinating enzyme (DUB), contains an N-terminal-disordered alanine -, proline -, glycine-rich region (APGR), a catalytic OTU domain, and a ubiquitin-interacting motif (UIM). It preferentially hydrolyzes lysine-63-linked ubiquitin chains and is involved in regulating multiple cellular functions, such as the NF-κB, KEAP1-NRF2, and Notch2-ICD signaling pathways, and plays a role in various biological processes including inflammation, oxidative stress response, cell death, and immune responses [4,6,7]. Gene knockout mouse models have been crucial for studying its functions in vivo.

In mouse models, Otud1 knockout significantly protected against angiotensin II-induced cardiac dysfunction, hypertrophy, fibrosis, and inflammatory response, as well as transverse aortic constriction (TAC)-induced cardiac remodeling, suggesting its role in promoting pathological cardiac remodeling and heart failure by deubiquitinating STAT3 [1]. In colitis models, loss of Otud1 in mice contributed to the pathogenesis of dextran sulfate sodium (DSS)-induced colitis via excessive release of pro-inflammatory cytokines [2]. In cerebral ischemic injury models, Otud1 deficiency exacerbated injury due to inflammation induced by RIP2 ubiquitination [3]. In hepatic ischemia/reperfusion injury models, Otud1 alleviated oxidative stress, apoptosis, and inflammation by deubiquitinating and activating NRF2 [5]. In acute graft-versus-host disease (aGVHD) models, OTUD1 promoted the differentiation and functions of Th1 and Th17 cells, amplifying the aGVHD cascade [7].

In conclusion, Otud1 is a key regulator in multiple biological processes. Model-based research, especially through gene knockout mouse models, has revealed its role in various disease conditions including heart failure, colitis, cerebral ischemic injury, hepatic ischemia/reperfusion injury, and aGVHD. Understanding Otud1's functions provides potential therapeutic targets for these diseases.

References:

1. Wang, Mengyang, Han, Xue, Yu, Tianxiang, Wang, Yi, Liang, Guang. 2023. OTUD1 promotes pathological cardiac remodeling and heart failure by targeting STAT3 in cardiomyocytes. In Theranostics, 13, 2263-2280. doi:10.7150/thno.83340. https://pubmed.ncbi.nlm.nih.gov/37153745/

2. Wu, Bo, Qiang, Lihua, Zhang, Yong, Liu, Cui Hua, Zhang, Lingqiang. 2021. The deubiquitinase OTUD1 inhibits colonic inflammation by suppressing RIPK1-mediated NF-κB signaling. In Cellular & molecular immunology, 19, 276-289. doi:10.1038/s41423-021-00810-9. https://pubmed.ncbi.nlm.nih.gov/34876703/

3. Zheng, Shengnan, Li, Yiquan, Song, Xiaomeng, Chen, Lin, Liu, Huiqing. 2023. OTUD1 ameliorates cerebral ischemic injury through inhibiting inflammation by disrupting K63-linked deubiquitination of RIP2. In Journal of neuroinflammation, 20, 281. doi:10.1186/s12974-023-02968-7. https://pubmed.ncbi.nlm.nih.gov/38012669/

4. Oikawa, Daisuke, Shimizu, Kouhei, Tokunaga, Fuminori. 2023. Pleiotropic Roles of a KEAP1-Associated Deubiquitinase, OTUD1. In Antioxidants (Basel, Switzerland), 12, . doi:10.3390/antiox12020350. https://pubmed.ncbi.nlm.nih.gov/36829909/

5. Zhang, Qi, Chen, Zihan, Li, Jinglei, Zhang, Jinxiang, Wang, Hui. 2024. The deubiquitinase OTUD1 stabilizes NRF2 to alleviate hepatic ischemia/reperfusion injury. In Redox biology, 75, 103287. doi:10.1016/j.redox.2024.103287. https://pubmed.ncbi.nlm.nih.gov/39079388/

6. Oikawa, Daisuke, Gi, Min, Kosako, Hidetaka, Sawasaki, Tatsuya, Tokunaga, Fuminori. 2022. OTUD1 deubiquitinase regulates NF-κB- and KEAP1-mediated inflammatory responses and reactive oxygen species-associated cell death pathways. In Cell death & disease, 13, 694. doi:10.1038/s41419-022-05145-5. https://pubmed.ncbi.nlm.nih.gov/35941131/

7. Cheng, Qiao, Wang, Dong, Lai, Xiaoxuan, Wu, Depei, Xu, Yang. . The OTUD1-Notch2-ICD axis orchestrates allogeneic T cell-mediated graft-versus-host disease. In Blood, 141, 1474-1488. doi:10.1182/blood.2022017201. https://pubmed.ncbi.nlm.nih.gov/36574342/