The Emerging Role and Mechanism of E2/E3 Hybrid Enzyme UBE2O in Human Diseases

Abstract

The ubiquitin-proteasome system (UPS) plays a pivotal role in determining protein fate, regulating signal transduction, and maintaining cellular homeostasis. Protein ubiquitination, a key post-translational modification, is orchestrated by the sequential actions of three primary enzymes, ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin protein ligase (E3), alongside the regulatory influence of deubiquitinases (DUBs) and various cofactors. The process begins with E1, which activates ubiquitin molecules. Subsequently, E2 receives the activated ubiquitin from E1 and transfers it to E3. E3, in turn, recognizes specific target proteins and facilitates the covalent attachment of ubiquitin from E2 to lysine residues on the target protein. Among the E2 enzymes, ubiquitin-conjugating enzyme E2O (UBE2O) stands out as a unique E2-E3 hybrid enzyme. UBE2O directly mediates the ubiquitination of a wide array of substrates, including 5'-AMP-activated protein kinase catalytic subunit alpha-2 (AMPKα2), MAX interactor 1 (Mxi1), and v-maf musculoaponeurotic fibrosarcoma oncogene homolog (c-Maf), among others. In this narrative review, we will explore the structural characteristics of UBE2O and elucidate its molecular functions. Additionally, we will summarize recent advancements in understanding the role of UBE2O in various tumors, Alzheimer's disease (AD), and metabolic diseases. Finally, we will discuss the potential of targeting UBE2O as a novel therapeutic strategy for the treatment of human diseases.

Keywords: Alzheimer’s disease; UBE2O; hematologic malignancies; metabolic diseases; solid tumors; substrates.

Figure 1

Domain architecture of UBE2O. The UBE2O protein (1292 amino acids) comprises three conserved regions (CR1, CR2, CR3), a ubiquitin-conjugating (UBC) domain, and two nuclear localization sequences (NLSs). The CR1 and CR2 domains mediate substrate binding, whereas the UBC domain facilitates interactions with multiple E3 ligases. Catalytic activation sites are localized to Cys-1040 (E2) and Cys-617 (E3) residues, respectively.

Figure 2

In cancer, UBE2O regulates primary substrates such as AMPKα2, MIXL1, HADHA, PLEKHG4, L3MBTL2, MLL, and c-Maf, among others. UBE2O is indicated by a purple box, while its downstream proteins are marked with green boxes. In tumors, UBE2O with pro-oncogenic functions is highlighted in yellow boxes, whereas UBE2O exhibiting tumor-suppressive roles is annotated with blue boxes.

Figure 3

In non-neoplastic diseases, UBE2O targets key substrates such as AMPKα2 and AβPP. UBE2O is represented by a purple box, and its downstream proteins are denoted by green boxes. In non-neoplastic diseases, UBE2O with inhibitory functions is highlighted in blue boxes.