Ube4a, encoding a U-box-type ubiquitin ligase, is a mammalian homolog of Saccharomyces cerevisiae Ufd2. It functions in ubiquitination-mediated regulation of protein targets, which is involved in various cellular functions and associated with multiple pathways such as insulin signaling, proteasome gene expression, and DNA damage response [1,2,4]. Its dysregulation is linked to diseases like obesity, NAFLD/NASH, intellectual disability, and cancer, highlighting its biological importance. Genetic models, especially mouse models, have been crucial for studying its in vivo functions [1,3].

A whole-body Ube4A knockout (UKO) mouse model showed that Ube4A is essential for maintaining metabolic homeostasis. UKO mice had mild hyperinsulinemia and insulin resistance even on a chow diet, which was exacerbated on a high-fat diet (HFD). HFD-fed UKO mice also had increased adipose tissue insulin resistance, inflammation, reduced energy metabolism, and more severe hepatic steatosis, inflammation, and liver injury. Mechanistically, Ube4A interacts with the Akt activator APPL1, and its absence impairs K63-linked ubiquitination of Akt and APPL1, thus disrupting insulin-induced Akt activation [1]. Additionally, mice mimicking patient-specific Ube4a loss-of-function variants exhibited muscular and neurological/behavioral abnormalities, indicating Ube4A's role in normal development and neurological function [3].

In conclusion, model-based research reveals that Ube4A is a key regulator of metabolism, insulin signaling, and normal development. The Ube4A KO mouse models have contributed significantly to understanding its role in obesity, insulin resistance, adipose tissue dysfunction, NAFLD, and intellectual disability, providing potential targets for treating these diseases.

References:

1. Mukherjee, Sandip, Chakraborty, Molee, Msengi, Eliwaza N, Neuschwander-Tetri, Brent A, Chakraborty, Anutosh. 2023. Ube4A maintains metabolic homeostasis and facilitates insulin signaling in vivo. In Molecular metabolism, 75, 101767. doi:10.1016/j.molmet.2023.101767. https://pubmed.ncbi.nlm.nih.gov/37429524/

2. Hu, Xianyan, Zou, Rong, Zhang, Zaihui, Zhang, Xiaoli, Zhang, Zai-Rong. 2023. UBE4A catalyzes NRF1 ubiquitination and facilitates DDI2-mediated NRF1 cleavage. In Biochimica et biophysica acta. Gene regulatory mechanisms, 1866, 194937. doi:10.1016/j.bbagrm.2023.194937. https://pubmed.ncbi.nlm.nih.gov/37084817/

3. Melo, Uirá Souto, Bonner, Devon, Kent Lloyd, Kevin C, Kok, Fernando, Byers, Heather M. 2021. Biallelic UBE4A loss-of-function variants cause intellectual disability and global developmental delay. In Genetics in medicine : official journal of the American College of Medical Genetics, 23, 661-668. doi:10.1038/s41436-020-01047-z. https://pubmed.ncbi.nlm.nih.gov/33420346/

4. Baranes-Bachar, Keren, Levy-Barda, Adva, Oehler, Judith, Ziv, Yael, Shiloh, Yosef. . The Ubiquitin E3/E4 Ligase UBE4A Adjusts Protein Ubiquitylation and Accumulation at Sites of DNA Damage, Facilitating Double-Strand Break Repair. In Molecular cell, 69, 866-878.e7. doi:10.1016/j.molcel.2018.02.002. https://pubmed.ncbi.nlm.nih.gov/29499138/