A Novel Pathway of Cell Death in Response to Cytosolic DNA in <b><i>Drosophila</i></b> Cells

Defence against invading DNA occurs in both mammals and bacteria. Recognition of stray DNA can initiate responses to infection, but may also protect against potentially mutagenic integration of transposons or retrotransposons into the genome. Double-stranded DNA detected in the cytosol of mammalian macrophages can elicit inflammatory cytokines and cell death following assembly of the AIM2 inflammasome. Amongst eukaryotes, responses to cytosolic DNA have so far only been detected in mammals, and AIM2 is mammalian restricted. In protecting genome integrity, we reasoned that pathways recognising invading DNA should be fundamental to cellular life, and that cell death would be an appropriate response to an overwhelming foreign DNA burden. We found that Drosophila S2 cells were killed by transfection of DNA from a range of natural sources. Unlike with mammalian cells, responses were not prevented by DNA denaturation. There was an element of sequence specificity, as synthetic single-stranded homopolymers were not toxic, whilst mixed-base synthetic DNA caused significant cell death. Death occurred with rapid loss of membrane integrity, and without the characteristic features of apoptosis. We have defined a novel defence against invading DNA in Drosophila. An active necrotic pathway has not previously been described in insects.