Recently it has been shown that the proinflammatory pathway promotes effective influenza virus propagation. Based on these findings, it was suggested that blockade might be a promising method for antiviral intervention. The classical virus-induced activation of the pathway calls for proteasomal degradation of the inhibitor. For that reason, we hypothesized that inhibition of proteasomal degradation should really impair influenza A virus (IAV) replication. We chose the particular proteasome inhibitor PS-341 which is a clinically approved anti-cancer drug also identified as Bortezomib or Velcade?. As expected, PS-341 therapy of infected A549 cells in a concentration range that was not toxic resulted in a considerable reduction of progeny virus titers. Even so, we could not observe the proposed suppression of NF-|¨ºB-signaling in vitro. PS-341 treatment rather resulted in an induction of of NF-|¨ºB-signaling in vitro. PS-341 remedy rather resulted in an induction of I|¨ºB degradation and activation of the NF-|¨ºB as well as the JNK/AP-1 pathway. This coincides with enhanced expression of antiviral genes such as IL-6 and, most importantly, MxA, that is a robust interferon (IFN)-induced suppressor of influenza virus replication. This suggests that PS-341 could act antiviral via an induction of the type I IFN response. Accordingly, PS-341 did not impact virus titers in Vero cells, which lack kind I IFN genes but strongly inhibited replication of vesicular stomatitis virus (VSV), a extremely IFN-sensitive pathogen. Therefore we conclude that PS-341 blocks IAV and VSV replication by inducing an antiviral state mediated by the NF-|¨ºB-dependent expression of antiviral acting gene goods. This study was in portion supported by distinctive grants of the Deutsche Forschungsgemeinschaft (DFG graduate school GRK1409, DFG Lu477/12-1) and by he German FluResearchNet, a nationwide analysis network on zoonotic influenza sponsored by the Ministry of Education and Investigation (BMBF).