ADAR1 isoforms are adenosine deaminases that edit and destabilize double-stranded RNA reducing its immunostimulatory activities. Mutation of leads to a severe neurodevelopmental and inflammatory disease of children, Aicardi-Goutiéres syndrome. In mice, mutations are embryonic lethal but are rescued by mutation of the or genes, which function in IFN induction. However, the specific IFN regulated proteins responsible for the pathogenic effects of mutation are unknown. We show that the cell-lethal phenotype of deletion in human lung adenocarcinoma A549 cells is rescued by CRISPR/Cas9 mutagenesis of the gene or by expression of the RNase L antagonist, murine coronavirus NS2 accessory protein. Our result demonstrate that ablation of RNase L activity promotes survival of ADAR1 deficient cells even in the presence of MDA5 and MAVS, suggesting that the RNase L system is the primary sensor pathway for endogenous dsRNA that leads to cell death.