The UBE2D ubiquitin conjugating enzymes: Potential regulatory hubs in development, disease and evolution

Abstract

Ubiquitination of cellular proteins plays critical roles in key signalling pathways and in the regulation of protein turnover in eukaryotic cells. E2 ubiquitin conjugating enzymes function as essential intermediates in ubiquitination reactions by acting as ubiquitin donors for the E3 ubiquitin ligase enzymes that confer substrate specificity. The members of the UBE2D family of E2 enzymes are involved in regulating signalling cascades through ubiquitination of target proteins that include receptor tyrosine kinases (RTKs) and components of the Hedgehog, TGFβ and NFκB pathways. UBE2D enzymes also function in transcriptional control by acting as donors for ubiquitination of histone tails by the Polycomb protein Ring1B and the DNA methylation regulator UHRF1 as well as having roles in DNA repair and regulation of the level of the tumour suppressor p53. Here we review the functional roles and mechanisms of regulation of the UBE2D proteins including recent evidence that regulation of the level of UBE2D3 is critical for controlling ubiquitination of specific targets during development. Cellular levels of UBE2D3 have been shown to be regulated by phosphorylation, which affects folding of the protein, reducing its stability. Specific variations in the otherwise highly conserved UBE2D3 protein sequence in amniotes and in a subgroup of teleost fishes, the Acanthomorpha, suggest that the enzyme has had important roles during vertebrate evolution.

High-grade serous carcinoma of the fallopian tube in a young woman with chromosomal 4q abnormality: A case report

“…Several of the genes involved may be associated with HGSC. The ubiquitin-conjugating enzyme E2 D3 (UBE2D3) gene encodes the UBE2D3 protein (Ubc5Hc), which regulates ubiquitination[ 24 ]. Ubiquitination targets proteins for proteasomal degradation and requires the thioester cascade of the E1-E2-E3 complex to transfer ubiquitin to target proteins[ 25 ].…”

WRN Inhibition Leads to its Chromatin-Associated Degradation Via the PIAS4-RNF4-p97/VCP Axis

“…4c and Extended Data Fig. 4c) (DiBello et al, 2016; Roman-Trufero and Dillon 2022). We also observed a rescue of the WRN degradation phenotype using SMT by measuring the density of WRN molecules after RNF4 siRNA knock-down (Extended Data Fig.…”