Bclaf1 critically regulates the type I interferon response and is degraded by alphaherpesvirus US3

Type I interferon response plays a prominent role against viral infection, which is frequently disrupted by viruses. Here, we report Bcl-2 associated transcription factor 1 (Bclaf1) is degraded during the alphaherpesvirus Pseudorabies virus (PRV) and Herpes simplex virus type 1 (HSV-1) infections through the viral protein US3. We further reveal that Bclaf1 functions critically in type I interferon signaling. Knockdown or knockout of Bclaf1 in cells significantly impairs interferon- (IFN) -mediated gene transcription and viral inhibition against US3 deficient PRV and HSV-1. Mechanistically, Bclaf1 maintains a mechanism allowing STAT1 and STAT2 to be efficiently phosphorylated in response to IFN, and more importantly, facilitates IFN-stimulated gene factor 3 (ISGF3) binding with IFN-stimulated response elements (ISRE) for efficient gene transcription by directly interacting with ISRE and STAT2. Our studies establish the importance of Bclaf1 in IFN-induced antiviral immunity and in the control of viral infections. Author summary Alphaherpesvirus, such as Pseudorabies virus (PRV) and Herpes simplex virus type 1 (HSV-1), can establish persistent infection and cause various diseases in hosts. Interferon (IFN) response is hosts' first defense system against viral infection. Here, we report alphaherpesvirus induces degradation of a host protein, Bclaf1, via its expressed viral protein US3 upon infection. We further show that Bclaf1 is a novel regulator of IFN pathway by enhancing the IFN induced transcriptions of anti-viral genes. In the absence of Bclaf1, IFN induced anti-viral activity is greatly reduced. Our study highlight the importance of Bclaf1 in IFN mediated antiviral function and reveal a strategy employed by alphaherpesvirus to counteract hosts' defense.