Abstract

Nucleic acids are a key target for the innate immune response to pathogens and, while the mechanisms of RNA sensing are well established, receptors for DNA have only recently been discovered. Here we show that the DNA -dependent protein kinase (DNA-PK) acts as an intracellular DNA sensor. DNA -PK bound to DNA in the cytoplasm and the absence of Ku or DNA -PKcs resulted in impaired transcription of type I interferon (IFN), cytokine and chemokine genes following DNA stimulation. DNA -PK binds IFN regulatory factor 3 (IRF-3) and is required to initiate IRF -3-dependent signalling in response to DNA via a pathway involving TANK binding kinase 1 (TBK1) and stimulator of interferon genes (STING). The importance of this pathway in sensing virus infection is shown by the observations that in cells infected with modified vaccinia Ankara (MVA) Ku70 and DNA -PKcs are associated with sites of viral DNA replication, and MVA infection of cells lacking DNA -PK components induced attenuated cytokine responses and increased virus protein expression. DNA -PK has a long-established role in DNA double-strand break repair in the nucleus and its loss causes a severe combined immune deficiency (SCID) phenotype, but here we describe a novel anti-microbial function for this complex.