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UBP43 (also known as ISG43, Ubl thiolesterase 18, ISG15-specific processing protease, 43 kDa ISG15-specific protease, ubiquitin specific protease 18 or USP18) is a member of the deubiquitinating protease family of enzymes, which removes ubiquitin adducts from a broad range of protein substrates. Deletion of the UBP43 gene in mouse leads to a massive increase of ISG15 conjugates in tissues indicating that UBP43 is a major ISG15-specific protease. UBP43 is the first ISG15-specific protease reported. Both ISG15 and UBP43 genes are known to be strongly induced by interferon, genotoxic stress, and viral infection. Thus UBP43 may be necessary to maintain a critical cellular balance of ISG15-conjugated proteins in both healthy and stressed organisms.