New Insights into the Role of E2s in the Pathogenesis of Diseases: Lessons Learned from UBE2O

Abstract

Intracellular communication via ubiquitin (Ub) signaling impacts all aspects of cell biology and regulates pathways critical to human development and viability; therefore aberrations or defects in Ub signaling can contribute to the pathogenesis of human diseases. Ubiquitination consists of the addition of Ub to a substrate protein via coordinated action of E1-activating, E2-conjugating and E3-ligating enzymes. Approximately 40 E2s have been identified in humans, and most are thought to be involved in Ub transfer; although little information is available regarding the majority of them, emerging evidence has highlighted their importance to human health and disease. In this review, we focus on recent insights into the pathogenetic roles of E2s (particularly the ubiquitin-conjugating enzyme E2O [UBE2O]) in debilitating diseases and cancer, and discuss the tantalizing prospect that E2s may someday serve as potential therapeutic targets for human diseases.

Keywords: E2 ubiquitin-conjugating enzyme; E3 ubiquitin ligase; UBE2O; pathogenesis; ubiquitination.

Fig. 1. Structural representation of E2s

Crystal structure of human UBE2D2(Protein Data Bank (PDB) code 2CLW) as a representative of the UBC fold conserved among E2s. The UBC core is comprised of four α-helices (pink colored) and an antiparallel β-sheet formed by four β-strands (yellow colored). The N- and C–termini of the domain are indicated. The location of the E3-binding site (L1 loop and L2 loop) and the active site cysteine (Cys85)(L3 loop) are also indicated.

Fig. 2. Classification of E2s

Four classes of E2s are depicted in different colored boxes upon the absence (class I) or presence of additional extensions in the N- or C–terminal of the UBC domain (class II or class III, respectively) or in both termini (class IV).

Fig. 3. Scheme of UBE2O functional domains

Shown are CR1 (conserved region 1), CR2 (conserved region 2), CR3 (conserved region 3), CC (coiled-coil domain) and UBC (ubiquitin-conjugating domain) containing an active site cysteine (Cys1040). Two putative nuclear localization signals and multiple predicted phosphorylation sites are also indicated.

Fig. 4. Pathogenetic roles ofUBE2O

(Top) A central role of UBE2O for erythropoiesis. UBE2O confers the erythroid differentiation through promoting the ubiquitination of free ribosomal proteins (1) and unassembled α-globin (2) and thereby remodeling the differentiation-linked proteome. (Bottom) An oncogenic role of UBE2O in cancer. UBE2O ubiquitinates and promotes ubiquitination and degradation of wild-type MLL but not MLL fusion proteins in MLL leukemia (1). Furthermore, UBE2O promotes mTOR− and HIF1α–mediated tumorigenesis through selectively targeting the AMPKα2 protein (2).