The close sequence relationship between USP5 and USP13 (61.4% identity, 26.9% similarity) is contrasted by the functional differences and localization of these two proteases. These enzymes provide a unique opportunity to investigate the structural features that may contribute to ubiquitin versus ubiquitin-like specificity. A characteristic of USP5 and USP13 is the tandem occurrence of a UBA domain, which has been implicated in the binding of ubiquitin [49] . Our results raise the possibility that UBA domains in general interact not only with ubiquitin, but also with ISG15. Alternatively, ISG15 with its multiple lysines could act as a ubiquitination anchor, and USP5 may be a protease responsible for depolymerization of such chains [50, 51] . Moreover, the Cterminal hydrolase that processes the ISG15 precursor has not been identified yet, and any of the novel ISG15-specific proteases described here are potential candidates.