Ubiquitin carboxyl-terminal hydrolase isozyme L3

UCHL3 (ubiquitin carboxyl-terminal hydrolase isozyme L3) is a deubiquitinating enzyme that processes ubiquitin precursors and ubiquitinated proteins, with a preference for lysine-48-linked chains (UniProt: P15374). It regulates membrane recycling, modulates insulin signaling through IGFIR/AKT/FOXO1 phosphorylation, and supports stress-response maintenance in retinal, skeletal muscle, and germ cells. Notably, it can degrade UBB(+1), a mutated ubiquitin form implicated in neurodegeneration.

UCHL3 has been associated with working memory function and carries potential relevance to neurodegenerative disease pathways through its role in ubiquitin homeostasis (UniProt: P15374). In Alzheimer's Disease, UCHL3 shows ambiguous regulation across brain subcellular fractions, with a mean log2 fold-change of −0.29 in post-mortem AD tissue versus age-matched controls using TMT proteomics across four subcellular fractions (Chaparral AD proteomics). This modest mean change masks opposing direction in individual fractions, limiting clear interpretation of AD-related dysregulation.