Usp33, also known as VDU1, is a deubiquitinating enzyme (DUB) that plays crucial roles in multiple biological processes and diseases. It is involved in pathways such as mitophagy, TGF-β signaling, and is associated with the regulation of proteins like p53, HIF-2α, and others, which are central to cell survival, proliferation, and response to stress [1,3,4,5]. Genetic models, especially gene knockout (KO) or conditional knockout (CKO) mouse models, can be valuable for further elucidating its functions.

In mitophagy, USP33 deficiency enhanced K48-and K63-linked PRKN ubiquitination, leading to increased PRKN protein stabilization and translocation to depolarized mitochondria, enhancing mitophagy. This indicates its role as an antagonist of PRKN-mediated mitophagy [1]. In ovarian cancer, USP33 was found to eliminate K27-and K48-linked ubiquitin chains from CBX2, promoting ovarian cancer proliferation and metastasis [2]. In pancreatic cancer, USP33 overexpression promoted cell proliferation, migration, and invasion by deubiquitinating TGFBR2 and activating the TGF-β signaling pathway [3]. In hepatocarcinogenesis, mice with hepatocyte-specific USP33 knockout were more sensitive to DEN-induced carcinogenesis, suggesting USP33 has anti-tumour activity via regulating p53 stability [4].

In conclusion, USP33 is a significant deubiquitinating enzyme involved in multiple biological processes, especially those related to cell survival, proliferation, and cancer progression. The use of KO/CKO mouse models has provided important insights into its role in diseases such as Parkinson's disease, various cancers, and non-alcoholic fatty acid disease-associated fibrosis [1-5]. These findings highlight its potential as a therapeutic target for these conditions.

References:

1. Niu, Kaifeng, Fang, Hongbo, Chen, Zixiang, Balajee, Adayabalam S, Zhao, Yongliang. 2019. USP33 deubiquitinates PRKN/parkin and antagonizes its role in mitophagy. In Autophagy, 16, 724-734. doi:10.1080/15548627.2019.1656957. https://pubmed.ncbi.nlm.nih.gov/31432739/

2. Chen, Jiming, Shan, Wulin, Jia, Qiucheng, Wang, Zengying, Xia, Bairong. 2024. USP33 facilitates the ovarian cancer progression via deubiquitinating and stabilizing CBX2. In Oncogene, 43, 3170-3183. doi:10.1038/s41388-024-03151-9. https://pubmed.ncbi.nlm.nih.gov/39256572/

3. Liu, Xinyuan, Xu, Jian, Shen, Bingbing, Xu, Jichuan, Jiang, Jianxin. 2023. USP33 promotes pancreatic cancer malignant phenotype through the regulation of TGFBR2/TGFβ signaling pathway. In Cell death & disease, 14, 362. doi:10.1038/s41419-023-05871-4. https://pubmed.ncbi.nlm.nih.gov/37322017/

4. Zhu, Yuqi, Chen, Zixiang, Niu, Kaifeng, Wang, Jiaqi, Zhao, YongLiang. 2024. USP33 Regulates DNA Damage Response and Carcinogenesis Through Deubiquitylating and Stabilising p53. In Cell proliferation, , e13793. doi:10.1111/cpr.13793. https://pubmed.ncbi.nlm.nih.gov/39694539/

5. Zhang, Aili, Huang, Zhi, Tao, Weiwei, Zhou, Wenchao, Bao, Shideng. 2022. USP33 deubiquitinates and stabilizes HIF-2alpha to promote hypoxia response in glioma stem cells. In The EMBO journal, 41, e109187. doi:10.15252/embj.2021109187. https://pubmed.ncbi.nlm.nih.gov/35191554/