USP25

USP28 is a deubiquitinase (DUB). Three isoforms of USP25 are generated by alternative splicing. Isoform USP25a is found in most adult and fetal tissues. Isoform USP25b is found in all tissues except heart and skeletal muscle. Isoform USP25m is specifically present in the skeletal muscle and heart and is upregulated during myogenesis. Like most USPs, USP25 has three ubiquitin-binding domains (UBDs) at the N terminus: a ubiquitin-associated domain (UBA) and two tandem ubiquitin-interacting motifs (UIMs). However, no clear structural homology among USP family members has been detected in the extended C-terminal region outside of the catalytic domain. Compared to the more common USP25a and USP25b isoforms, USP25m has an added muscle-specific domain. USP25 is not only distributed in the nucleus and cytoplasm but also can be localized to the endoplasmic reticulum (ER), where it negatively regulates ER-associated degradation (ERAD). USP25 as an essential DUB required for pancreatic ductal adenocarcinoma (PDAC) tumor growth and viability.