Fig. 6. Cellular sensing of extracellular purine nucleosides triggers an innate immune response.

Loss of extracellular ADA2 activity or an excess of extracellular purine nucleosides drives uptake of dAdo and intracellular catabolism by ADA1, yielding dIno, an immune-metabolite that directly inhibits MAT activity, the methionine cycle, and DNA methylation. Genomic hypomethylation drives up-regulation of ERV, dsRNA molecules that engage cytosolic dsRNA sensors RIG-I and MDA5 via the signaling adaptor MAVS.