Josd2, or Josephin domain-containing protein 2, is a deubiquitinating enzyme (DUB) that plays a crucial role in maintaining the stability of substrate proteins. It is involved in multiple cellular processes through regulating various signaling pathways such as the Wnt, MAPK/ERK, and PI3K/AKT pathways. Its functions are essential in normal cell physiology and are also closely associated with disease development, making genetic models like gene knockout (KO) mice valuable for studying its functions [1-10].

In KO mouse models, Josd2 deficiency aggravated cardiac dysfunction and hypertrophy, indicating its protective role in the heart [1,4]. In NSCLC, depletion of Josd2 significantly impeded tumor growth [2]. In cholangiocarcinoma, the depletion of Josd2 promoted YAP/TAZ proteasomal degradation and inhibited cancer cell proliferation [3]. In acute myeloid leukemia, re-constitution of Josd2 in cells with low expression inhibited cell viability and induced apoptosis [5]. In hepatocellular carcinoma, esophageal squamous cell carcinoma, and breast cancer, down-regulation of Josd2 suppressed tumor-related phenotypes such as cell survival, migration, invasion, and proliferation [6,7,9]. In contrast, in colitis, Josd2 deficiency exacerbated the disease phenotypes by enhancing colon inflammation [8].

In conclusion, Josd2 has diverse functions in different biological processes and disease conditions. Through model-based research, especially KO mouse models, we've learned that Josd2 can act as a tumor promoter in many cancers, while it has a protective role in some non-cancerous diseases like colitis. Understanding Josd2's functions provides potential therapeutic targets for treating hypertrophic cardiomyopathy, various cancers, and inflammatory bowel disease.

References:

1. Han, Jibo, Fang, Zimin, Han, Bingjiang, Wang, Yi, Liang, Guang. 2023. Deubiquitinase JOSD2 improves calcium handling and attenuates cardiac hypertrophy and dysfunction by stabilizing SERCA2a in cardiomyocytes. In Nature cardiovascular research, 2, 764-777. doi:10.1038/s44161-023-00313-y. https://pubmed.ncbi.nlm.nih.gov/39195964/

2. Yuan, Tao, Zeng, Chenming, Liu, Jiawei, He, Qiaojun, Yang, Bo. 2024. Josephin domain containing 2 (JOSD2) promotes lung cancer by inhibiting LKB1 (Liver kinase B1) activity. In Signal transduction and targeted therapy, 9, 11. doi:10.1038/s41392-023-01706-y. https://pubmed.ncbi.nlm.nih.gov/38177135/

3. Qian, Meijia, Yan, Fangjie, Wang, Weihua, Zhu, Hong, He, Qiaojun. 2021. Deubiquitinase JOSD2 stabilizes YAP/TAZ to promote cholangiocarcinoma progression. In Acta pharmaceutica Sinica. B, 11, 4008-4019. doi:10.1016/j.apsb.2021.04.003. https://pubmed.ncbi.nlm.nih.gov/35024322/

4. Xu, Jiachen, Liang, Shiqi, Wang, Qinyan, Zhou, Hao, Liang, Guang. 2024. JOSD2 mediates isoprenaline-induced heart failure by deubiquitinating CaMKIIδ in cardiomyocytes. In Cellular and molecular life sciences : CMLS, 81, 18. doi:10.1007/s00018-023-05037-7. https://pubmed.ncbi.nlm.nih.gov/38195959/

5. Lei, Hu, Yang, Li, Wang, Yingying, Xu, Hanzhang, Wu, Yingli. 2022. JOSD2 regulates PKM2 nuclear translocation and reduces acute myeloid leukemia progression. In Experimental hematology & oncology, 11, 42. doi:10.1186/s40164-022-00295-w. https://pubmed.ncbi.nlm.nih.gov/35836282/

6. Huang, Yao, Zeng, Jianxing, Liu, Teng, Song, Xianglin, Zeng, Jinhua. 2022. Deubiquitinating enzyme JOSD2 promotes hepatocellular carcinoma progression through interacting with and inhibiting CTNNB1 degradation. In Cell biology international, 46, 1089-1097. doi:10.1002/cbin.11812. https://pubmed.ncbi.nlm.nih.gov/35568970/

7. Wang, Wen-Peng, Shi, Dan, Yun, Duo, Wang, Jun-Feng, Kong, Da-Lu. . Role of deubiquitinase JOSD2 in the pathogenesis of esophageal squamous cell carcinoma. In World journal of gastroenterology, 30, 565-578. doi:10.3748/wjg.v30.i6.565. https://pubmed.ncbi.nlm.nih.gov/38463028/

8. Liu, Xin, Fang, Yi, Huang, Mincong, Wang, Yi, Liang, Guang. 2024. Deubiquitinase JOSD2 alleviates colitis by inhibiting inflammation via deubiquitination of IMPDH2 in macrophages. In Acta pharmaceutica Sinica. B, 15, 1039-1055. doi:10.1016/j.apsb.2024.12.012. https://pubmed.ncbi.nlm.nih.gov/40177575/

9. Du, Jiamin, Wang, Jiao, Ge, Fujing, Yuan, Tao, Zhu, Hong. 2025. JOSD2 promotes breast cancer metastasis by deubiquitinating and stabilizing SMAD4. In Biochemical pharmacology, 232, 116748. doi:10.1016/j.bcp.2025.116748. https://pubmed.ncbi.nlm.nih.gov/39793716/