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

Yongxu Lu,Jennifer H Stuart,Callum Talbot-Cooper,Shuchi Agrawal-Singh,Brian Huntly,Andrei I Smid,Joseph S Snowden,Liane Dupont,Geoffrey L Smith

doi:10.1073/pnas.1816399116

Yongxu Lu, Jennifer H Stuart + Show 7 more

Open Access

https://doi.org/10.1073/pnas.1816399116

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Abstract

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 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 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.

Highlights

Dition of trichostatin A (TSA) [16] or the absence of HDAC1 [17, 18], HDAC2 [17], or HDAC3 [19]
This study reports that HDAC4 is required for type I IFN signaling and restricts the replication of herpes simplex virus type 1 (HSV-1) and vaccinia virus (VACV)
Given that HDAC4 is required for type I IFN signaling and coprecipitates with STAT2 via its transactivation domain (TAD), and VACV protein C6 has both these functions [36], we investigated if C6 was required for the degradation of HDAC4

Summary

Introduction

Dition of TSA [16] or the absence of HDAC1 [17, 18], HDAC2 [17], or HDAC3 [19]. HDAC1 coprecipitates with signal transducer and activator of transcription 1 (STAT1) and STAT2 [18]. HDAC1, HDAC2, and HDAC3 are required for type II IFN signaling [21]. | | | type I interferon signaling STAT2 recruitment histone deactylase 4 | vaccinia virus protein C6 immune evasion. HDACs can induce gene expression; for instance, in leukemic cells, similar numbers of genes are up- or down-regulated by the broad spectrum HDAC inhibitor trichostatin A (TSA) [2]. HDAC activity is important for signaling leading to IFN expression because this is blocked by TSA [7]. For HDAC3, different studies using different cell types reported either activation [12] or repression [13] of IFN-β expression. HDAC4 [14], HDAC1, and HDAC8 [8, 15] were reported to repress type I IFN expression

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