UBE2D3
Description
The UBE2D3 (ubiquitin conjugating enzyme E2 D3) is a protein-coding gene located on chromosome 4.
Ubiquitin-conjugating enzyme E2 D3 is a protein that in humans is encoded by the UBE2D3 gene. The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: ubiquitin-activating enzymes, or E1s, ubiquitin-conjugating enzymes, or E2s, and ubiquitin-protein ligases, or E3s. This gene encodes a member of the E2 ubiquitin-conjugating enzyme family. This enzyme functions in the ubiquitination of the tumor-suppressor protein p53, which is induced by an E3 ubiquitin-protein ligase. Multiple spliced transcript variants have been found for this gene, but the full-length nature of some variants has not been determined. UBE2D3 has been shown to interact with NEDD4.
UBE2D3, also known as E3-independent E2 ubiquitin-conjugating enzyme D3, E2 ubiquitin-conjugating enzyme D3, Ubiquitin carrier protein D3, Ubiquitin-conjugating enzyme E2(17)KB 3, Ubiquitin-conjugating enzyme E2-17 kDa 3, Ubiquitin-protein ligase D3, accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. It can catalyze both Lys-11- and Lys-48-linked polyubiquitination in vitro. UBE2D3 cooperates with the E2 CDC34 and the SCF(FBXW11) E3 ligase complex for the polyubiquitination of NFKBIA, leading to its subsequent proteasomal degradation. It acts as an initiator E2, priming phosphorylated NFKBIA at Lys-21 and/or Lys-22 with monoubiquitin. Ubiquitin chain elongation is then performed by CDC34, building ubiquitin chains from the UBE2D3-primed NFKBIA-linked ubiquitin. UBE2D3 also acts as an initiator E2, in conjunction with RNF8, for priming PCNA. Monoubiquitination of PCNA and its subsequent polyubiquitination are essential events in the DNA damage tolerance (DDT) pathway, activated after DNA damage caused by UV or chemical agents during S-phase. UBE2D3 associates with the BRCA1/BARD1 E3 ligase complex to perform ubiquitination at DNA damage sites following ionizing radiation, leading to DNA repair. It targets DAPK3 for ubiquitination, which influences promyelocytic leukemia protein nuclear body (PML-NB) formation in the nucleus. In conjunction with MDM2 and TOPORS E3 ligases, UBE2D3 functions in the ubiquitination of p53/TP53. With the CBL E3 ligase, it targets EGFR for polyubiquitination at the plasma membrane as well as during its internalization and transport on endosomes. Working with the STUB1 E3 quality control E3 ligase, UBE2D3 ubiquitinates unfolded proteins to catalyze their immediate destruction. Together with RNF135, UBE2D3 catalyzes viral RNA-dependent Lys-63-linked polyubiquitination of RIGI to activate the downstream signaling pathway leading to interferon beta production. In conjunction with ZNF598, UBE2D3 catalyzes ubiquitination of 40S ribosomal proteins in response to ribosome collisions. In cooperation with the GATOR2 complex, UBE2D3 catalyzes Lys-6-linked ubiquitination of NPRL2. UBE2D3 interacts with the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex. When Cullin is neddylated, the interaction between the E2 and the SCF complex is strengthened. UBE2D3 also interacts with DAPK3, BRCA1 (where the DNA damage checkpoint promotes the association with BRCA1 after ionizing radiation), and ubiquitin non-covalently. Other interactions include E3 ubiquitin-protein ligase CBLC, UBTD1, and RIGI and RNF135 (involved in RIGI ubiquitination and activation).
UBE2D3 is also known as E2(17)KB3, UBC4/5, UBCH5C.
