Ube2o, an atypical ubiquitin-conjugating enzyme, has an E2-E3 hybrid enzyme activity. It is involved in regulating substrate levels or transcriptional activities by collaborating with other E3 ubiquitin ligases or forming homomeric complexes with intrinsic E2 and E3 activities. Ube2o is crucial for controlling the cell proteome quality, including protein degradation, modification, transport, and location, and is associated with multiple signaling pathways like BMP/SMAD, TRAF/NF-κB, mTOR/HIF1a, and IL-1β/IRAK4 [3].

In hepatocellular carcinoma (HCC), Ube2o deficiency inhibits tumor growth and metastasis both in vitro and in vivo. Ube2o can interact with and mediate the ubiquitination and degradation of HADHA, a mitochondrial β-oxidation enzyme, modulating lipid metabolic reprogramming [2]. Also, in HCC, knockdown of Ube2o enhances the efficacy of interferon-α by upregulating IFIT3 expression as IFIT3 is a ubiquitination substrate of Ube2o [1]. In osteosarcoma, multi-monoubiquitination of L3MBTL2 by Ube2o results in its proteasomal degradation, and the Ube2o/L3MBTL2 axis is crucial for tumor growth [4]. Pharmacological blockage of Ube2o can suppress osteosarcoma growth. In lung cancer, genetical or pharmacological blockade of Ube2o impairs tumor progression and radioresistance by preventing the ubiquitination and degradation of Mxi1 [5]. In Alzheimer's disease, age-associated reduction of Ube2o may facilitate neuronal death, and increasing its expression can rescue amyloid-β protein precursor (AβPP)-induced neuronal death [6].

In conclusion, Ube2o plays essential roles in multiple biological processes and disease conditions. Through gene knockout or conditional knockout mouse models and other loss-of-function experiments, it has been revealed that Ube2o is involved in tumorigenesis, metastasis, interferon-α efficacy, radioresistance, and neurodegeneration. These findings suggest that targeting Ube2o could be a potential therapeutic approach for treating related diseases such as HCC, osteosarcoma, lung cancer, and Alzheimer's disease.

References:

1. Li, Heng, Liu, Yao, Cheng, Can, Wang, Jia-Bei, Liu, Lian-Xin. 2023. UBE2O reduces the effectiveness of interferon-α via degradation of IFIT3 in hepatocellular carcinoma. In Cell death & disease, 14, 854. doi:10.1038/s41419-023-06369-9. https://pubmed.ncbi.nlm.nih.gov/38129382/

2. Ma, Meilin, Zhang, Changhui, Cao, Rong, Gao, Xiang, Fu, Xianghui. 2022. UBE2O promotes lipid metabolic reprogramming and liver cancer progression by mediating HADHA ubiquitination. In Oncogene, 41, 5199-5213. doi:10.1038/s41388-022-02509-1. https://pubmed.ncbi.nlm.nih.gov/36273042/

3. Lv, Yi, Xing, Feiyue. 2022. Regulatory roles of an atypical ubiquitin ligase UBE2O in orphans of multiprotein complexes for degradation. In Turkish journal of biology = Turk biyoloji dergisi, 46, 186-194. doi:10.3906/biy-2106-63. https://pubmed.ncbi.nlm.nih.gov/37533513/

4. Zhong, Li, Wang, Jingxuan, Chen, Wanqi, Kang, Tiebang, Liao, Dan. 2023. Augmenting L3MBTL2-induced condensates suppresses tumor growth in osteosarcoma. In Science advances, 9, eadi0889. doi:10.1126/sciadv.adi0889. https://pubmed.ncbi.nlm.nih.gov/37992172/

5. Huang, Yumei, Yang, Xijie, Lu, Yanwei, Xu, Shuangbing, Wu, Gang. 2020. UBE2O targets Mxi1 for ubiquitination and degradation to promote lung cancer progression and radioresistance. In Cell death and differentiation, 28, 671-684. doi:10.1038/s41418-020-00616-8. https://pubmed.ncbi.nlm.nih.gov/32901121/

6. Cheng, Jing, Zheng, Huancheng, Liu, Chenyu, Xing, Zhenkai, Wu, Yili. . Age-Associated UBE2O Reduction Promotes Neuronal Death in Alzheimer's Disease. In Journal of Alzheimer's disease : JAD, 93, 1083-1093. doi:10.3233/JAD-221143. https://pubmed.ncbi.nlm.nih.gov/37182872/