PKR and the Integrated Stress Response drive immunopathology caused by ADAR1 mutation

Summary Mutations in ADAR , the gene that encodes the ADAR1 RNA deaminase, cause numerous human diseases, including Aicardi-Goutières Syndrome (AGS). ADAR1 is an essential negative regulator of the RNA sensor MDA5, and loss of ADAR1 function triggers inappropriate activation of MDA5 by self-RNAs. However, the mechanisms of MDA5-dependent disease pathogenesis in vivo remain unknown. Here, we introduce a knockin mouse that models the most common ADAR AGS mutation in humans. These Adar -mutant mice develop lethal disease that requires MDA5, the RIG-I-like receptor LGP2, type I interferons, and the eIF2α kinase PKR. We show that a small molecule inhibitor of the integrated stress response (ISR) that acts downstream of eIF2α phosphorylation prevents immunopathology and rescues the mice from mortality. These findings place PKR and the ISR as central components of immunopathology in vivo and identify new therapeutic targets for treatment of human diseases associated with the ADAR1-MDA5 axis.