UBE3B is a HECT-domain E3 ubiquitin ligase located on chromosome 12.1 that catalyzes K63-linked polyubiquitination of target proteins 1. The enzyme functions as a mitochondrion-associated protein regulated by calmodulin through its N-terminal IQ motif, with calcium signaling modulating its activity 2. UBE3B ubiquitinates branched-chain α-ketoacid dehydrogenase kinase (BCKDK), regulating metabolic pathways including nucleotide metabolism and the tricarboxylic acid cycle 3. In cancer contexts, UBE3B promotes breast tumor growth by preventing VHL-mediated HIF-2α degradation through K63-linked polyubiquitination at lysine residues 394, 497, and 503 4, though VHL reciprocally targets UBE3B for K48-linked polyubiquitination and proteasomal degradation 5. Biallelic UBE3B mutations cause Kaufman oculocerebrofacial syndrome (KOS), an autosomal-recessive neurodevelopmental disorder featuring intellectual disability, developmental delay, growth retardation, and low cholesterol levels 6. Loss of UBE3B in mice recapitulates KOS pathology, including corpus callosum hypoplasia, abnormal dendritic morphology, and altered mitochondrial respiration 3. Recent evidence associates rare UBE3B variants with age-related hearing loss 7, broadening its clinical relevance beyond neurometabolic disease.