Histone deacetylase 4 promotes type I interferon signaling, restricts DNA viruses, and is degraded via vaccinia virus protein C6.
Stuart, Jennifer H
Proceedings of the National Academy of Sciences of the United States of America
National Academy of Sciences
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Lu, Y., Stuart, J. H., Talbot-Cooper, C., Agrawal-Singh, S., Huntly, B., Smid, A., Snowden, J. S., et al. (2019). Histone deacetylase 4 promotes type I interferon signaling, restricts DNA viruses, and is degraded via vaccinia virus protein C6.. Proceedings of the National Academy of Sciences of the United States of America, 116 (24), 11997-12006. https://doi.org/10.1073/pnas.1816399116
Interferons (IFNs) represent an important host defence against viruses. Type I IFNs induce JAKSTAT signaling and expression of interferon-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 re-introduction of HDAC4 or catalytically inactive HDAC4, but not HDAC1 or HDAC5. ChIP analysis showed HDAC4 bound to ISG promoters following IFN stimulation, and was 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 33 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.
Cell Line, Cell Line, Tumor, Hela Cells, Humans, DNA Viruses, Herpesvirus 1, Human, Vaccinia virus, Vaccinia, Histone Deacetylases, Interferon Type I, Repressor Proteins, Viral Proteins, Virus Replication, Signal Transduction, HEK293 Cells
This work was supported by the Wellcome Trust. GLS is a Wellcome Trust Principal Research Fellow. Yongxu Lu, Andrei I. Smid, Jennifer H. Stuart and Liane Dupont were supported by the Wellcome Trust, Joseph S. Snowden was supported by the Lister Institute and Callum Talbot-Cooper was supported by the BBSRC.
Wellcome Trust (090315/B/09/Z)
WELLCOME TRUST (090315/B/09/A)
External DOI: https://doi.org/10.1073/pnas.1816399116
This record's URL: https://www.repository.cam.ac.uk/handle/1810/292681
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