A search for the primary DNA virus receptor has fueled much research over the past years. From the discovery of DAI, a protein that seemed critical for DNA induced IFN to the in vivo
finding that DAI may be redundant, many groups have searched for the “key” DNA receptor or sought to understand how DNA recognition occurs5,6
. A major development is the discovery that the protein STING is necessary for IFN induction by exposure to B-DNA and the DNA virus HSV-17,8
. STING is an ER-localized, multi-transmembrane domain protein that interacts with IRF-3, TBK1, CARDIF and RIG-I, and seems to coordinate the signaling of IFN induction. Though, this protein is not a DNA receptor, STING deficient mice represents one of the first knockouts that are compromised in IFN induction capacity by all exogenous DNA or DNA viruses.
In the past year, the hypothesis that the DNA receptor directly binds to DNA was found to be insufficient. Two reports show that rather than DNA recognition, RNA transcribed from cytoplasmic DNA can function as a ligand for RIG-I induced IFN9
. Here abundant cytoplasmic DNA containing AT-rich regions can be transcribed by RNA Polymerase III (RNAP3) and the RNA transcripts are recognized by the RIG-I pathway, in effect turning viral DNA into RNA PAMPs. RNAP3 is important in cells transfected with B-DNA or infected at high MOI with HSV-19
. Epstein-Barr Virus (EBV) also transcribes small RNAs via RNAP3 from viral DNA into RIG-I ligands. Whether RNAP3 transcription of viral DNA is physiologically relevant remains an central question.