Ube2j2-KO Mouse

Ube2j2, an ubiquitin-conjugating enzyme, is a component of the ubiquitin-proteasome system. It responds to proteotoxic stress and functions in the ubiquitination of proteins at the endoplasmic reticulum (ER) [1,4]. Ubiquitination by Ube2j2 is involved in multiple pathways, including endoplasmic reticulum-associated degradation (ERAD), and it has a significant impact on various biological processes and disease-related mechanisms [3].

Genome-wide CRISPR/Cas9 screens in a mouse AML line insensitive to Venetoclax-induced mitochondrial apoptosis found that depletion of Ube2j2 sensitized AML cells to Venetoclax in the presence of March5, suggesting a coordinate function of Ube2j2 and Ube2k with the E3 ligase March5 [2]. In hepatocellular carcinoma (HCC), Ube2j2 was highly expressed in metastatic HCC cells. Overexpression of Ube2j2 activated endothelial-mesenchymal transition and promoted invasion in non-invasive HCC cell lines, while its silencing reduced cell invasion and endocytosis and downregulated p-EGFR expression [1].

In conclusion, Ube2j2 plays crucial roles in biological processes such as ER-associated protein degradation and cell invasion. Its function in the context of acute myeloid leukemia and hepatocellular carcinoma, as revealed through functional studies including gene-knockout-like CRISPR/Cas9 screens, provides insights into disease mechanisms and potential therapeutic targets in these disease areas.

References:

1. Chen, Shaopeng, Tan, Ying, Deng, Haihua, Tan, Chunyan, Jiang, Yuyang. 2017. UBE2J2 promotes hepatocellular carcinoma cell epithelial-mesenchymal transition and invasion in vitro. In Oncotarget, 8, 71736-71749. doi:10.18632/oncotarget.17601. https://pubmed.ncbi.nlm.nih.gov/29069742/

2. Nakao, Fumihiko, Setoguchi, Kiyoko, Semba, Yuichiro, Akashi, Koichi, Maeda, Takahiro. 2023. Targeting a mitochondrial E3 ubiquitin ligase complex to overcome AML cell-intrinsic Venetoclax resistance. In Leukemia, 37, 1028-1038. doi:10.1038/s41375-023-01879-z. https://pubmed.ncbi.nlm.nih.gov/36973350/

3. Wang, Xiaoli, Herr, Roger A, Rabelink, Martijn, Wiertz, Emmanuel J H J, Hansen, Ted H. . Ube2j2 ubiquitinates hydroxylated amino acids on ER-associated degradation substrates. In The Journal of cell biology, 187, 655-68. doi:10.1083/jcb.200908036. https://pubmed.ncbi.nlm.nih.gov/19951915/

4. Lam, Shuet Y, Murphy, Claire, Foley, Louise A, Wang, Timothy C, Fleming, John V. 2014. The human ubiquitin conjugating enzyme UBE2J2 (Ubc6) is a substrate for proteasomal degradation. In Biochemical and biophysical research communications, 451, 361-6. doi:10.1016/j.bbrc.2014.07.099. https://pubmed.ncbi.nlm.nih.gov/25083800/