Ubiquitinating enzymes (UBEs) catalyze protein ubiquitination, a reversible process countered by deubiquitinating enzymes (DUB) action. There are five DUB subfamilies including the USP, UCH, OTU, MJD, and JAMM enzymes. USP25 (ubiquitin specific peptidase 25), also known as USP21, is a 1087 amino acid member of the peptidase C19 family. Expressed at high amounts in pancreas, kidney, skeletal muscle, testis, liver, heart, brain and lung, USP25 associates with the 26S proteasome and functions as a deubiquitinating enzyme in the Ub proteolytic pathway. Due to alternative splicing events, USP25 is expressed as two short, ubiquitously expressed isoforms and one long, muscle specific isoform. The long isoform of USP25 is upregulated in myogenesis and is implicated in the pathogenesis of severe myopathies.