Our data show the existence of multiple ISG15-reactive DUBs, a finding that further strengthens the similarities between ubiquitin and ISG15. USP2 is a highly active protease [37] and it represents one of only few mammalian DUBs with a known target. USP2 exhibits oncogenic potential in prostate cancer by stabilizing its substrate Fatty Acid Synthase (FAS) [38] , and FAS has indeed been identified as a target of ISG15 modification [39] . Furthermore, USP2 has been implicated in the regulation of the p53 pathway [40] . The recently solved structures of USP2 and USP14 [41, 42] show that both proteases accommodate the ubiquitin molecule in a shallow pan-like protrusion. Based on the orientation of the ubiquitin protein in both structures, ISG15 easily fits into the catalytic domain of USP2, USP14, and USP5 (data not shown) without apparent steric clashes (Figure 7 ) [23, 43] .