BRCA1-regulated nuclear innate sensing of Herpesviral genome by IFI16 and IFI16’s acetylation is critical for its cytoplasmic trafficking and induction of innate responses

Abstract

Sensing of invading DNA virus genomes appear to be triggered by a number of host cell DNA sensors depending on their subcellular localization which stimulate innate anti-viral responses such as the activation of type-I interferons (IFNs) and/or inflammasomes resulting in the  production of inflammatory IL-1β and IL-18 cytokines. With growing understanding of diverse identities whether these proteins function alone or  with other host cell molecules and the post-translational modifications affecting their functions are under intense investigations. Nuclear resident IFI16 have been shown to sense the episomal DNA genomes of herpes viruses resulting in the induction of IFI16-inflammasome and/or interferon responses. Here, we highlight our recent finding regarding the role of cellular  BRCA1, a transcription factor and DNA damage response protein, forming a distinct complex with IFI16 to regulate the nuclear innate sensing of herpes viral DNA and subsequent IFI16-ASC-procaspase-1 inflammasome complex formation and distribution to the cytoplasm leading into caspase-1 and IL-1β production. BRCA1 is also responsible for the cytoplasmic IFI16-STING signalosome activation and induction of IFN-β during de novo KSHV and HSV-1 infection. Our concurrent studies have also revealed that the histone acetyl transferase p300 mediated acetylation of nuclear IFI16 is a dynamic post-genome recognition event responsible for Ran dependent nuclear to cytoplasmic trafficking of IFI16 during herpesvirus infection. This post-translational modification is essential for IFI16-ASC interaction and inflammasome activation as well as for the association with STING in the cytoplasm resulting in IRF-3 phosphorylation, nuclear pIRF-3 localization and interferon-β production. Collectively, these comprehensive studies highlight that BRCA1 plays a hitherto unidentified immunomodulatory role to facilitate the anti-viral functions of IFI16 and acetylation of nuclear IFI16 is a necessary post-translational modification for innate responses during herpesvirus infection. These studies open up a new understanding of virus-host interplay, viral genome sensing and host innate anti-viral defense mechanisms.