Expression of the N-terminal part of the RNA-dependent RNA polymerase (L), which contains the OTU domain, was sufficient to reproduce the antagonistic effect on IFN induction in a reporter gene-based assay (fig. 5) , and we could show that mutations that affected the catalytic site of the OTU protease were no longer antagonists ( fig. 8 ). Ubiquitination and modification of cellular proteins with ubiquitin-like molecules such as ISG15 play important roles in regulating IFN induction through both the Toll-like receptor (TLR) and RIG-I-like receptor (RLR) pathways [46, 47] . Lys-63-linked polyubiquitination of RIG-I has been shown to be crucial for its ability to induce type I IFNs [48] . Arimoto et al. [49] showed that virus-induced IRF3 and NF-kB activation is dependent on the polyubiquitination of the protein NF-kB essential modulator (NEMO). Furthermore NF-kB activation is known to depend on ubiquitination of the inhibitor protein I-kB, targeting it for degradation [50] , while ISG15ylation enhances NF-kB activity by conjugating to and suppressing protein phosphatase 2Cb, which suppresses dephosphorylation of I-kB [51] . ISG15ylation positively regulates IRF-3 activation by preventing its interaction with PinI [52] . Wholesale removal of conjugated ubiquitin and ubiquitin-like modifiers would therefore greatly inhibit the IFN induction pathway. Indeed we observed a significant reduction in the levels of cellular ISG15-and ubiquitinconjugates during NSDV/GV infection ( fig. 7a, b) which could be attributed to the OTU domain of the L protein ( fig. 7c, d) . The enzymatic activity proved to be essential for the observed inhibition of IFN induction ( fig. 8e) .