We also found that NSDV is able to inhibit the action of type I and II IFNs, and that this activity involves the inhibition of phosphorylation of both STAT1 and STAT2. The mechanism(s) of this inhibition remains to be determined. There is no reduction in the levels of STAT1/2, and an inhibition of their phosphorylation suggests either binding/sequestration of one or both STATs or inhibition of the IFN receptor-associated JAKs. We observed that IFNc-induced STAT1 phosphorylation was blocked similarly by both isolates at all times post infection, whereas IFNainduced STAT1/2 phosphorylation was dependent the degree of growth of the virus, the block developing more slowly in cells infected with the slower-growing GV isolate. This suggests that the mechanisms by which the virus exerts the blockade of type I and 2 IFNs are not the same. Further evidence for this came from the GV L1-169 Q16R mutant, which retained most of its DUB activity and its full deISG15ylating activity and still shows significant blockade of IFNa-induced gene expression but no longer blocks IFNc-induced gene expression ( fig. 8c, d) . It could be that this part of the N-terminus contains a specific-substrate binding site in addition to the catalytic core of the OTU domain, contributing to the effect of the OTU domain on specific cellular substrates; in this case the Q16R mutation exerts a steric inhibition on binding to the target involved in blocking type II IFN action, rather than an inhibition which is dependent on the OTU enzymatic activity. For the herpesvirus-associated ubiquitinspecific protease (HAUSP or USP7), an additional binding site with affinity for its target protein has been described in addition to its catalytic protease domain [59] .