Nucleic Acid Sensing in Mammals and Plants: Facts and Caveats

The accumulation of nucleic acids in aberrant compartments is a signal of danger: fragments of cytosolic or extracellular self-DNA indicate cellular dysfunctions or disruption, whereas cytosolic fragments of nonself-DNA or RNA indicate infections. Therefore, nucleic acids trigger immunity in mammals and plants. In mammals, endosomal Toll-like receptors (TLRs) sense single-stranded (ss) or double-stranded (ds) RNA or CpG-rich DNA, whereas various cytosolic receptors sense dsDNA. Although a self/nonself discrimination could favor targeted immune responses, no sequence-specific sensing of nucleic acids has been reported for mammals. Specific immune responses to extracellular self-DNA versus DNA from related species were recently reported for plants, but the underlying mechanism remains unknown. The subcellular localization of mammalian receptors can favor self/nonself discrimination based on the localization of DNA fragments. However, autoantibodies and diverse damage-associated molecular patterns (DAMPs) shuttle DNA through membranes, and most of the mammalian receptors share downstream signaling elements such as stimulator of interferon genes (STING) and the master transcription regulators, nuclear factor (NF)-κB, and interferon regulatory factor 3 (IRF3). The resulting type I interferon (IFN) response stimulates innate immunity against multiple threats-from infection to physical injury or endogenous DNA damage-all of which lead to the accumulation of eDNA or cytoplasmatic dsDNA. Therefore, no or only low selective pressures might have favored a strict self/nonself discrimination in nucleic acid sensing. We conclude that the discrimination between self- and nonself-DNA is likely to be less strict-and less important-than assumed originally.