Ubiquitin-conjugating enzyme E2 L3 (UbcH7) (UbcH7)

Ubiquitin-conjugating enzyme E2 L3 (UbcH7), also known as UBE2L3, is a critical E2 enzyme within the ubiquitin-proteasome system (UPS) that facilitates the transfer of activated ubiquitin to substrate proteins [1, 9]. It is unique among E2 enzymes for its high specificity toward HECT-type and RBR (RING-Between-RING) family E3 ligases, such as Parkin and E6AP, while lacking intrinsic reactivity with most RING-type ligases [9, 11]. UbcH7 plays a pivotal role in regulating diverse cellular processes, including the NF-κB signaling pathway, cell cycle progression through the S-phase, and the transcriptional activity of nuclear hormone receptors [2, 3, 7]. Dysregulation or genetic polymorphisms of UBE2L3 are strongly associated with various autoimmune disorders, including systemic lupus erythematosus (SLE), rheumatoid arthritis, and Crohn's disease [6, 13, 32]. Additionally, it is implicated in the progression of several cancers and the pathogenesis of Parkinson's disease through its interaction with the E3 ligase Parkin [2, 11, 12]. As a result, UbcH7 has emerged as a promising therapeutic target for the development of modulators to treat immune-mediated and oncological diseases [1, 15]. Small-molecule inhibitors such as BAY 11-7082 have been identified to covalently inactivate the enzyme by targeting its catalytic cysteine residue, thereby blocking downstream signaling pathways like NF-κB [17, 22]. Therapeutic challenges include achieving selectivity over other E2 enzymes and managing potential systemic effects due to the enzyme's broad biological functions [1, 16].

Other names

UBE2L3L-UBCUbiquitin carrier protein L3Ubiquitin-conjugating enzyme E2-F1Ubiquitin-protein ligase L3UbcM4

Covalent inhibition of the catalytic cysteine residue and disruption of E2-E3 ligase interactions