We also examined the ability of L1-169 C40A, H151A, and Q16R to block type I ( fig. 8d) and II (fig. 8e ) IFN action. We used the same experimental setup as described before when we tested the different viral proteins for their ability to block IFN action ( fig. 6 ). The catalytic site mutants of L1-169 no longer blocked type I IFN-induced gene expression (fig. 8c) . The Q16R mutant did block the induced transcription from the Mx-1 promoter to some extent, but not as efficiently as the wildtype. All mutants lost their ability to block type II IFN-induced gene expression (fig. 8d) . These data show that the enzymatic activity of the OTU domain in the nairovirus L protein plays a pivotal role in antagonizing IFN induction and action. In addition, the data from the Q16R mutant strongly suggests that specific, yet different, targets are involved in antagonising these three activities, since this protein is still able to remove ubiquitin and ISG15 from the dominant cellular substrates, but lost its ability to antagonize IFN induction and type II IFN action while retaining some ability to block type I IFN action.