Ribonuclease L mediates the cell-lethal phenotype of double-stranded RNA editing enzyme ADAR1 deficiency in a human cell line.

Abstract

ADAR1 isoforms are adenosine deaminases that edit and destabilize double-stranded RNA reducing its immunostimulatory activities. Mutation of <i>ADAR1</i> leads to a severe neurodevelopmental and inflammatory disease of children, Aicardi-Goutiéres syndrome. In mice, <i>Adar1</i> mutations are embryonic lethal but are rescued by mutation of the <i>Mda5</i> or <i>Mavs</i> genes, which function in IFN induction. However, the specific IFN regulated proteins responsible for the pathogenic effects of <i>ADAR1</i> mutation are unknown. We show that the cell-lethal phenotype of <i>ADAR1</i> deletion in human lung adenocarcinoma A549 cells is rescued by CRISPR/Cas9 mutagenesis of the <i>RNASEL</i> 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.