Ube2e3-KO Mouse

Ube2e3, also known as UbcH9, is a ubiquitin-conjugating enzyme (E2) that plays a crucial role in the ubiquitination process, which is involved in many cellular processes such as protein degradation, cell cycle regulation, and DNA repair [7]. Ubiquitination requires the sequential action of E1, E2, and E3 enzymes, and Ube2e3 acts in concert with E3 enzymes in this pathway [5]. It is also associated with pathways related to cellular senescence, proliferation, and differentiation, and thus is of great biological importance. Genetic models, such as gene knockout (KO) in mice, can be valuable for studying its functions.

Depletion of Ube2e3 in cells induces cellular senescence in the absence of overt DNA damage, with distinct phenotypes like an increased senescence-associated secretory phenotype, mitochondrial and lysosomal mass, autophagic flux, and sensitivity to mitochondrial and lysosomal poisons [2]. In bone marrow mesenchymal stem cells (BMSCs), knockdown of Ube2e3 accelerates cellular senescence and inhibits osteogenic differentiation in young cells, while overexpression attenuates senescence and enhances osteogenic differentiation in old BMSCs, suggesting its potential involvement in osteoporosis pathogenesis [1]. In ovarian granulosa cells, miR-143-3p targets Ube2e3 to promote cell senescence and inhibit estradiol synthesis, indicating its role in ovarian aging [3]. In breast cancer cells, miR-379-5p targets Ube2e3, and silencing Ube2e3 leads to complex effects on cell viability, proliferation, and apoptosis [4]. In retinal pigment epithelial cells, depletion of Ube2e3 by siRNA causes cell-cycle exit, indicating its essentiality for cell proliferation [6].

In conclusion, Ube2e3 is essential for regulating cellular senescence, proliferation, and differentiation processes. Studies using gene-knockout models have revealed its role in diseases such as osteoporosis, ovarian aging, and potentially in breast cancer. Understanding Ube2e3 functions provides insights into the underlying mechanisms of these biological processes and diseases, which may contribute to the development of novel therapeutic strategies.

References:

1. Liu, Yalin, Cai, Guangping, Chen, Peng, Jiang, Tiejian, Xia, Zhuying. 2021. UBE2E3 regulates cellular senescence and osteogenic differentiation of BMSCs during aging. In PeerJ, 9, e12253. doi:10.7717/peerj.12253. https://pubmed.ncbi.nlm.nih.gov/34820159/

2. Plafker, Kendra S, Zyla, Katarzyna, Berry, William, Plafker, Scott M. 2018. Loss of the ubiquitin conjugating enzyme UBE2E3 induces cellular senescence. In Redox biology, 17, 411-422. doi:10.1016/j.redox.2018.05.008. https://pubmed.ncbi.nlm.nih.gov/29879550/

3. Deng, Jingxian, Tang, Yan, Li, Lu, Yang, Yan, Huang, Yadong. 2023. miR-143-3p Promotes Ovarian Granulosa Cell Senescence and Inhibits Estradiol Synthesis by Targeting UBE2E3 and LHCGR. In International journal of molecular sciences, 24, . doi:10.3390/ijms241612560. https://pubmed.ncbi.nlm.nih.gov/37628741/

4. Schroder, Araya K, Loy, Conor J, Aiala, Fernanda, Ghosh, Arnob, Yoo, Lina I. 2024. miR-379-5p affects breast cancer cell behavior by targeting UBE2E3 ubiquitin conjugating enzyme. In PloS one, 19, e0310315. doi:10.1371/journal.pone.0310315. https://pubmed.ncbi.nlm.nih.gov/39621672/

5. Debonneville, Christophe, Staub, Olivier. . Participation of the ubiquitin-conjugating enzyme UBE2E3 in Nedd4-2-dependent regulation of the epithelial Na+ channel. In Molecular and cellular biology, 24, 2397-409. doi:. https://pubmed.ncbi.nlm.nih.gov/14993279/

6. Plafker, Kendra S, Farjo, Krysten M, Wiechmann, Allan F, Plafker, Scott M. 2008. The human ubiquitin conjugating enzyme, UBE2E3, is required for proliferation of retinal pigment epithelial cells. In Investigative ophthalmology & visual science, 49, 5611-8. doi:10.1167/iovs.08-1698. https://pubmed.ncbi.nlm.nih.gov/18614808/

7. Ito, K, Kato, S, Matsuda, Y, Kimura, M, Okano, Y. . cDNA cloning, characterization, and chromosome mapping of UBE2E3 (alias UbcH9), encoding an N-terminally extended human ubiquitin-conjugating enzyme. In Cytogenetics and cell genetics, 84, 99-104. doi:. https://pubmed.ncbi.nlm.nih.gov/10343118/