UBE3C is an E3 ubiquitin ligase that catalyzes Lys-29- and Lys-48-linked polyubiquitin chains on substrate proteins, accepting ubiquitin from the E2 enzyme UBE2D1 and transferring it to targeted substrates. The protein associates with the proteasome and promotes elongation of ubiquitin chains on substrates bound to the 26S proteasome. UBE3C regulates multiple cellular processes through substrate ubiquitination. It acts as a negative regulator of autophagy by mediating ubiquitination of PIK3C3/VPS34, promoting its degradation. It also suppresses type I interferon responses by catalyzing ubiquitination and proteasomal degradation of IRF3 and IRF7. Recent evidence suggests that UBE3C plays a temporal role in antiviral immunity: early after viral infection, the deubiquitinase BAP1 stabilizes IRF3, but later, interferon-β induces UBE3C to ubiquitinate and degrade IRF3, resolving the antiviral response 1. Additionally, UBE3C contributes to acute protein aggregate turnover in a proteasome-dependent manner independent of RPN13 ubiquitylation 2. Pathogenic biallelic variants in UBE3C cause neurodevelopmental disorders overlapping with Angelman syndrome, with loss-of-function mutations identified in affected families 3. UBE3C is elevated in multiple cancer types and promotes progression: in osteosarcoma through ferroptosis suppression via AHNAK degradation 4, in pancreatic ductal adenocarcinoma through p53 ubiquitination 5, and in clear cell renal cell carcinoma through PEBP1 degradation and ERK pathway activation 6. A complex structural variation creating a UBE3C intergenic fusion causes distal hereditary motor neuropathy through defective protein homeostasis 7.