Induction of interferon-stimulated gene expression and antiviral responses require protein deacetylase activity

Abstract

Histone deacetylase (HDAC) activity, commonly correlated with transcriptional repression, was essential for transcriptional induction of IFN-stimulated genes (ISG). Inhibition of HDAC function led to global impairment of ISG expression, with little effect on basal expression. HDAC function was not required for signal transducer and activator of transcription tyrosine phosphorylation, nuclear translocation, or assembly on chromatin, but it was needed for full activity of the signal transducer and activator of transcription transactivation domain. HDAC function was also required for gene induction driven by the IFN regulatory factor 3 transcription factor activated by virus infection, and it was essential for establishment of an antiviral response against Flaviviridae, Rhabdoviridae, and Picornaviridae. Requirement for HDAC function in transcriptional activation may represent a general mechanism for rapid stimulation of ISG transcription.

Chemical targeting of the innate antiviral response by histone deacetylase inhibitors renders refractory cancers sensitive to viral oncolysis

“…We reasoned that combining a viral therapeutic with a compound that reversibly compromises host antiviral genetic programs could provide a means to enhance OV growth in tumor cells. Histone deacetylase inhibitors (HDIs) are small molecules currently in clinical development that have demonstrated potent anti-tumor activity but are also known to prevent the transcriptional activation of antiviral genes after IFN stimulation or virus infection (12)(13)(14)(15)(16)(17)(18)(19). Here, we demonstrate that a variety of HDIs markedly enhance OV killing of tumor cells in vitro and in vivo but do not increase OV growth in normal tissues.…”

The type I interferon system in systemic lupus erythematosus

“…Several possible target molecules exist, with inhibitors of Tyk-2 being one example. In addition, the transcription of IFN-stimulated genes could be blocked by histone deacetylase inhibitors (116,117). In fact, such drugs can reduce glomerulonephritis in the MLR-lpr/lpr mouse (118).…”

Cockayne syndrome group B protein (CSB) plays a general role in chromatin maintenance and remodeling

“…Most cells, including these CS fibroblasts, express low but detectable levels of IFNs that are thought to be critical for priming robust induction of IFNs in response to viral infection (46). Intriguingly, HDAC activity is required for IFN-induced, but not basal, expression of IFN target genes (47). The relatively low expression of IFN-induced genes in CSB-null cells may indicate that induction by IFNs is both HDAC-and CSB-dependent, consistent with our observation that HDAC inhibitors phenocopy loss of CSB, and that both cause dysfunctional chromatin remodeling.…”