Ubiquitin specific protease 18 (USP18/UBP43) is the major ISG15 deconjugating enzyme. It removes ISG15 from ISGylated proteins. ISG15-specific protease activity of this enzyme is crucial for proper cellular balance of ISG15-conjugated proteins. However, it is not required for processing pre-ISG15 to the mature form. Furthermore, USP18 inhibits type I interferon signaling independent of its ISG15 deconjugating enzyme activity. Several viral proteins were also reported with de-ISGylation activity.