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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 24; pp. 11997 - 12006
• Main Authors: Lu, Yongxu, Stuart, Jennifer H., Talbot-Cooper, Callum, Agrawal-Singh, Shuchi, Huntly, Brian, Smid, Andrei I., Snowden, Joseph S., Dupont, Liane, Smith, Geoffrey L.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11.06.2019
• Series: PNAS Plus
• Subjects: Antiviral activity; Biological Sciences; Cell Line; Cell Line, Tumor; Degradation; Deoxyribonucleic acid; DNA; DNA viruses; DNA Viruses - metabolism; Gene expression; HEK293 Cells; HeLa Cells; Herpes simplex; Herpesvirus 1, Human - metabolism; Histone deacetylase; Histone Deacetylases - metabolism; Histones; Humans; Interferon; Interferon Type I - metabolism; Pharmacology; PNAS Plus; Promoters; Proteasomes; Proteins; Reintroduction; Repressor Proteins - metabolism; Signal Transduction - physiology; Signaling; Stat2 protein; Vaccinia - metabolism; Vaccinia - virology; Vaccinia virus - metabolism; Viral Proteins - metabolism; Virus Replication - physiology; Viruses; α-Interferon; vaccinia virus protein C6; histone deactylase 4; STAT2 recruitment; immune evasion; type I interferon signaling
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1816399116

Interferons (IFNs) represent an important host defense against viruses. Type I IFNs induce JAK-STAT signaling and expression of IFN-stimulated genes (ISGs), which mediate antiviral activity. Histone deacetylases (HDACs) perform multiple functions in regulating gene expression and some class I HDACs and the class IV HDAC, HDAC11, influence type I IFN signaling. Here, HDAC4, a class II HDAC, is shown to promote type I IFN signaling and coprecipitate with STAT2. Pharmacological inhibition of class II HDAC activity, or knockout of HDAC4 from HEK-293T and HeLa cells, caused a defective response to IFN-α. This defect in HDAC4−/− cells was rescued by reintroduction of HDAC4 or catalytically inactive HDAC4, but not HDAC1 or HDAC5. ChIP analysis showed HDAC4 was recruited to ISG promoters following IFN stimulation andwas needed for binding of STAT2 to these promoters. The biological importance of HDAC4 as a virus restriction factor was illustrated by the observations that (i) the replication and spread of vaccinia virus (VACV) and herpes simplex virus type 1 (HSV-1) were enhanced in HDAC4−/− cells and inhibited by overexpression of HDAC4; and (ii) HDAC4 is targeted for proteasomal degradation during VACV infection by VACV protein C6, a multifunctional IFN antagonist that coprecipitates with HDAC4 and is necessary and sufficient for HDAC4 degradation.