Histone deacetylase 4 promotes type I interferon signaling, restricts DNA virus replication and is 1 degraded via vaccinia virus protein C6 2

Interferons (IFNs) represent an important host defence against viruses. Type I IFNs induce JAK- 21 STAT signaling and expression of interferon-stimulated genes (ISGs), which mediate antiviral 22 activity. Histone deacetylases (HDACs) perform multiple functions in regulating gene 23 expression and some class I HDACs and the class IV HDAC, HDAC11, influence type I IFN 24 signaling. Here, HDAC4, a class II HDAC, is shown to promote type I IFN signaling and co- 25 precipitate with STAT2. Pharmacological inhibition of class II HDAC activity, or knockout of 26 HDAC4 from HEK-293T and HeLa cells, caused a defective response to IFN- α . This defect in 27 HDAC4 -/- cells was rescued by re-introduction of HDAC4 or catalytically inactive HDAC4, but 28 not HDAC1 or HDAC5. ChIP analysis showed HDAC4 bound to ISG promoters following IFN 29 stimulation, and was needed for binding of STAT2 to these promoters. The biological replication and spread of vaccinia (VACV) and herpes simplex virus type (HSV-1) were enhanced in HDAC4 -/- cells and inhibited by over-expression of HDAC4; and ii) HDAC4 is targeted for proteasomal degradation during VACV infection by VACV protein C6, a multifunctional IFN antagonist, that co-precipitates with HDAC4 and is necessary and sufficient for HDAC4 degradation.