U-box domain, a modified RING finger, found in ubiquitin conjugation factor E4 B (UBE4B) and similar proteins
UBE4B, also known as UFD2a, is a U-box-type ubiquitin-protein ligase that functions as an E3 ubiquitin ligase and an E4 polyubiquitin chain elongation factor, which catalyzes formation of Lys27- and Lys33-linked polyubiquitin chains rather than the Lys48-linked chain. It is a mammalian homolog of yeast UFD2 ubiquitination factor and participates in the proteasomal degradation of misfolded or damaged proteins through association with chaperones. It is located in common neuroblastoma deletion regions and may be subject to mutations in tumors. UBE4B has contradictory functions upon tumorigenesis as an oncogene or tumor suppressor in different types of cancers. It is essential for Hdm2 (also known as Mdm2)-mediated p53 degradation. It mediates p53 polyubiquitination and degradation, as well as inhibits p53-dependent transactivation and apoptosis, and thus plays an important role in regulating phosphorylated p53 following DNA damage. UBE4B is also associated with other pathways independent of the p53 family, such as polyglutamine aggregation and Wallerian degeneration, both of which are critical in neurodegenerative diseases. Moreover, UBE4B acts as a regulator of epidermal growth factor receptor (EGFR) degradation. It is recruited to endosomes in response to EGFR activation by binding to Hrs, a key component of endosomal sorting complex required for transport (ESCRT) 0, and then regulates endosomal sorting, affecting cellular levels of the EGFR and its downstream signaling. UBE4B contains a ubiquitin elongating factor core and a RING-like U-box domain at the C-terminus.