The IL-1β and
type I interferon-β (IFN-β) molecules are important inflammatory
cytokines elicited by the eukaryotic host as innate immune responses against invading pathogens and danger signals. Recently, a predominantly nuclear
gamma-interferon-inducible
protein 16 (IFI16) involved in transcriptional regulation has emerged as an innate
DNA sensor which induced IL-1β and IFN-β production through
inflammasome and
STING activation, respectively. Herpesvirus (KSHV, EBV, and HSV-1) episomal dsDNA genome recognition by IFI16 leads to IFI16-ASC-procaspase-1
inflammasome association, cytoplasmic translocation and IL-1β production. Independent of ASC, HSV-1 genome recognition results in IFI16 interaction with
STING in the cytoplasm to induce
interferon-β production. However, the mechanisms of IFI16-inflammasome formation, cytoplasmic redistribution and
STING activation are not known. Our studies here demonstrate that recognition of herpesvirus genomes in the nucleus by IFI16 leads into its interaction with
histone acetyltransferase p300 and IFI16 acetylation resulting in IFI16-ASC interaction,
inflammasome assembly, increased interaction with Ran-
GTPase, cytoplasmic redistribution, caspase-1 activation, IL-1β production, and interaction with
STING which results in IRF-3 phosphorylation, nuclear pIRF-3 localization and
interferon-β production. ASC and
STING knockdowns did not affect IFI16 acetylation indicating that this modification is upstream of
inflammasome-assembly and
STING-activation. Vaccinia virus replicating in the cytoplasm did not induce nuclear IFI16 acetylation and cytoplasmic translocation. IFI16 physically associates with KSHV and HSV-1 genomes as revealed by proximity
ligation microscopy and
chromatin-immunoprecipitation studies which is not hampered by the inhibition of acetylation, thus suggesting that acetylation of IFI16 is not required for its innate sensing of nuclear viral genomes. Collectively, these studies identify the increased nuclear acetylation of IFI16 as a dynamic essential post-genome recognition event in the nucleus that is common to the IFI16-mediated innate responses of
inflammasome induction and IFN-β production during herpesvirus (KSHV, EBV, HSV-1)
infections.