The C-terminal six amino acids of ubiquitin and ISG15 are identical. This tail region is required for specific recognition of ubiquitin by conjugating enzymes, and also for recognition of ubiquitin adducts by isopeptidases [22, 23] . The overlap in conjugation between ubiquitin and ISG15, as well as their Cterminal similarity, imply the existence of promiscuous DUBs, capable of removing both ubiquitin and ISG15 from substrate proteins. Here, we report on the identification of new ISG15specific proteases measured by reactivity toward active-site directed probes and isopeptide-linked substrates [24] [25] [26] .