Abstract: Ubiquitination is an important post-translational modification (PTMs), regulating several cellular functions. UBE4B, a kind of E3 ubiquitin ligase enzyme, belongs to the U-box family that contains a characteristic U-box domain of about 70 amino acids, which directly recognizes specific substrates during the ubiquitination. UBE4B has a special E4 activity, which can drive polyubiquitin chain assembly with E1, E2, and E3. UBE4B plays a critical role in life processes such as embryonic development and neuron protection. It can also degrade a variety of substrates with important physiological functions, such as p53, EGFR, FEZ1 and Ataxin-3. UBE4B is related to the occurrence and development of cancer, neurodegeneration diseases and obesity. The study of UBE4B is of great significance for disease treatment and new drug development. This review demonstrated the structural characteristics, physiological functions, related diseases, and substrates of UBE4B, elaborating the research progress of UBE4B in the past two decades and providing theoretical guidance for further study of UBE4B.

Key words: ubiquitination, E3 ubiquitin ligases, UBE4B, U-box, E4