The innate immune system pattern recognition receptors (PRR) are the first line 
of host defenses recognizing the various pathogen- or danger-associated 
molecular patterns and eliciting defenses by regulating the production of 
pro-inflammatory cytokines such as IL-1β, IL-18 or interferon β (IFN-β). 
NOD-like receptors (NLRs) and AIM2-like receptors (ALRs) are cytoplasmic 
inflammasome sensors of foreign molecules, including DNA. IFI16, a 
sequence-independent nuclear innate sensor ALR, recognizes episomal dsDNA 
genomes of herpes viruses such as KSHV, EBV, and HSV-1 in the infected cell 
nuclei, forms an inflammasome complex with ASC and procaspase1, and relocates 
into the cytoplasm leading into Caspase-1 and IL-1β generation. IFI16 also 
induces IFN-β during HSV-1 infection via the cytoplasmic STING-TBK1-IRF3 
pathway. Thus far, whether IFI16 recognizes foreign DNA directly or utilizes 
other host protein(s) is unknown. Here, we demonstrate that BRCA1, a DNA damage 
repair sensor and transcription regulator, is in complex with IFI16 in the host 
cell nucleus, and their association increases in the presence of nuclear viral 
genomes during de novo KSHV, EBV and HSV-1 infection, and in latent KSHV or EBV 
infection, but not by DNA damage responses (DDR) induced by bleomycin and 
vaccinia virus cytoplasmic dsDNA. BRCA1 is a constituent of the triggered 
IFI16-inflammasome and is translocated into the cytoplasm after genome 
recognition along with the IFI16-inflammasome. The absence of BRCA1 abrogated 
IFI16-viral genome association, inflammasome assembly, IFI16 cytoplasmic 
localization, and Caspase-1 and IL-1β production. The absence of BRCA1 also 
abolished the cytoplasmic IFI16-STING interaction, downstream IRF3 
phosphorylation, nuclear translocation of pIRF3 and IFN-β production during de 
novo KSHV and HSV-1 infection. These findings highlight that BRCA1 plays a 
hitherto unidentified innate immunomodulatory role by facilitating nuclear 
foreign DNA sensing by IFI16, subsequent assembly and cytoplasmic distribution 
of IFI16-inflammasomes leading into IL-1β formation and the induction of IFN-β 
via cytoplasmic signaling through IFI16-STING, TBK1 and IRF3.