Pseudorabies Virus Inhibits Type I and Type III Interferon-Induced Signaling via Proteasomal Degradation of Janus Kinases

Both type I and III interferons (IFNs) play a crucial role in host antiviral response by activating the JAK/STAT (Janus kinase/signal transducer and activator of transcription) signaling pathway to trigger the expression of antiviral IFN-stimulated genes (ISGs). We report that the porcine alphaherpesvirus pseudorabies virus (PRV) triggers proteasomal degradation of the key Janus kinases Jak1 and to a lesser extent Tyk2, thereby inhibiting both type I and III IFN-induced STAT1 phosphorylation and suppressing IFN-induced expression of ISGs. UV-inactivated PRV did not interfere with IFN signaling. In addition, deletion of the EP0 gene from the PRV genome or inhibition of viral genome replication did not affect PRV-induced inhibition of IFN signaling. To our knowledge, this is the first report describing Janus kinase degradation by alphaherpesviruses. These findings thus reveal a novel alphaherpesvirus evasion mechanism of type I and type III IFNs. IMPORTANCE Type I and III interferons (IFNs) trigger signaling via Janus kinases that phosphorylate and activate signal transducer and activator of transcription (STAT) transcription factors, leading to the expression of antiviral interferon-stimulated genes (ISGs) that result in an antiviral state of host cells. Viruses have evolved various mechanisms to evade this response. Our results indicate that an alphaherpesvirus, the porcine pseudorabies virus (PRV), inhibits both type I and III IFN signaling pathways by triggering proteasome-dependent degradation of the key Janus kinases Jak1 and Tyk2 and consequent inhibition of STAT1 phosphorylation and suppression of ISG expression. Moreover, we found that this inhibition is not caused by incoming virions and does not depend on expression of the viral EP0 protein or viral true late proteins. These data for the first time address alphaherpesvirus evasion of type III IFN-mediated signaling and reveal a previously uncharacterized alphaherpesvirus mechanism of IFN evasion via proteasomal degradation of Janus kinases.