Oga-KO Mouse

Oga, short for O-GlcNAcase, is the only human enzyme catalyzing the hydrolysis (deglycosylation) of O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) from numerous protein substrates [1]. O-GlcNAcylation is a post-translational modification regulating diverse cellular processes such as signal transduction, cell cycle, metabolism, and energy homeostasis [3]. Dysregulation of O-GlcNAcylation, which Oga plays a crucial role in maintaining, has been implicated in various diseases including cancer, diabetes, and neurodegeneration [2,3].

In triple-negative breast cancer, adipocyte-derived exosomes promote tumor progression through circCRIM1-dependent OGA activation. OGA negatively regulates FBP1 by decreasing its protein stability, and the levels of OGA and FBP1 are related to immune cell infiltration [6]. In DNA damage repair, OGA is recruited to the sites of DNA damage, mediated by O-GlcNAcylation events. Its C-terminal truncated form with the pseudo HAT domain is required for recruitment and for recognizing and deglycosylating DNA repair factors like NONO and the Ku70/80 complex. Suppression of this deglycosylation impairs non-homologous end joining (NHEJ) [4]. In heart failure research, transgenic mouse models with myocardial overexpression of OGA had lower O-GlcNAcylation and were resistant to pathologic stress induced by pressure overload, with decreased pathologic hypertrophy compared to wild-type controls. This suggests enhanced OGA activity is beneficial against pressure overload-induced pathologic remodeling and heart failure [5].

In conclusion, Oga is essential for maintaining O-GlcNAcylation homeostasis, playing a significant role in processes like DNA damage repair, cancer progression, and heart failure. Studies using transgenic mouse models, including overexpression models related to Oga, have provided valuable insights into its functions in these disease-related biological processes, contributing to our understanding of disease mechanisms and potential therapeutic strategies.

References:

1. Hu, Chia-Wei, Wang, Ao, Fan, Dacheng, Li, Lingjun, Jiang, Jiaoyang. 2024. OGA mutant aberrantly hydrolyzes O-GlcNAc modification from PDLIM7 to modulate p53 and cytoskeleton in promoting cancer cell malignancy. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2320867121. doi:10.1073/pnas.2320867121. https://pubmed.ncbi.nlm.nih.gov/38838015/

2. Lu, Ping, Liu, Yusong, He, Maozhou, Yu, Hongtao, Gao, Haishan. 2023. Cryo-EM structure of human O-GlcNAcylation enzyme pair OGT-OGA complex. In Nature communications, 14, 6952. doi:10.1038/s41467-023-42427-8. https://pubmed.ncbi.nlm.nih.gov/37907462/

3. He, Xue-Fen, Hu, Xiaoli, Wen, Gao-Jing, Wang, Zhiwei, Lin, Wen-Jing. 2023. O-GlcNAcylation in cancer development and immunotherapy. In Cancer letters, 566, 216258. doi:10.1016/j.canlet.2023.216258. https://pubmed.ncbi.nlm.nih.gov/37279852/

4. Cui, Yaqi, Xie, Rong, Zhang, Xuefang, Yu, Xiaochun, Wu, Chen. 2021. OGA is associated with deglycosylation of NONO and the KU complex during DNA damage repair. In Cell death & disease, 12, 622. doi:10.1038/s41419-021-03910-6. https://pubmed.ncbi.nlm.nih.gov/34135314/

5. Umapathi, Priya, Mesubi, Olurotimi O, Banerjee, Partha S, Zachara, Natasha E, Anderson, Mark E. 2021. Excessive O-GlcNAcylation Causes Heart Failure and Sudden Death. In Circulation, 143, 1687-1703. doi:10.1161/CIRCULATIONAHA.120.051911. https://pubmed.ncbi.nlm.nih.gov/33593071/

6. Li, Yuehua, Jiang, Baohong, Zeng, Lijun, Zhu, Hongbo, Wu, Yimou. 2023. Adipocyte-derived exosomes promote the progression of triple-negative breast cancer through circCRIM1-dependent OGA activation. In Environmental research, 239, 117266. doi:10.1016/j.envres.2023.117266. https://pubmed.ncbi.nlm.nih.gov/37775001/