Protein ubiquitination and Deubiquitination are reversible processes catalyzed by ubiquitinating enzymes (UBEs) and deubiquitinating enzymes (DUBs). DUBs are categorized into 5 subfamilies: USP, UCH, OTU, MJD, and JAMM. UCHL1, UCHL3, UCHL5/UCH37, and BRCA-1-associated protein-1 (BAP1) belong to the UCH family of DUBs, which all possess a conserved catalytic domain (UCH domain) of about 230 amino acids. Although UCHL1 and UCHL3 are the most closely related UCH family members with about 53% identity, their biochemical properties differ in that UCHL1 binds monoubiquitin and UCHL3 shows dual specificity toward both ubiquitin (Ub) and NEDD8, a Ub-like molecule. UCHL3 is a thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of either ubiquitin or NEDD8. UCHL3 has a 10-fold preference for Arg and Lys at position P3. It deubiquitinates ENAC in the apical compartments, thereby regulating apical membrane recycling. UCHL3 indirectly increases the phosphorylation of IGFIR, AKT and FOXO1 and promotes insulin-signaling and insulin-induced adipogenesis. It is required for stress-response retinal, skeletal muscle and germ cell maintenance. UCHL3 may be involved in working memory.UCHL3 possesses 52% amino acid identity with UCHL1 and is uniformly expressed in all tissues, including the brain. The activity of UCHL3 is more than 200-fold higher than UCH-L1, as assessed with a fluorogenic ubiquitin substrate.