Protein kinase R and the integrated stress response drive immunopathology caused by mutations in the RNA deaminase ADAR1

The RNA deaminase ADAR1 is an essential negative regulator of the RNA sensor MDA5, and loss of ADAR1 function triggers inappropriate activation of MDA5 by self-RNAs. Mutations in ADAR, the gene that encodes ADAR1, cause human immune diseases, including Aicardi-Goutieres syndrome (AGS). However, the mechanisms of MDA5-dependent disease pathogenesis in vivo remain unknown. Here we generated mice with a single amino acid change in ADAR1 that models the most common human ADAR AGS mutation. These Adar mutant mice developed lethal disease that required MDA5, the RIG-I-like receptor LGP2, type I interferons, and the eIF2 alpha kinase PKR. A small-molecule inhibitor of the integrated stress response (ISR) that acts downstream of eIF2 alpha phosphorylation prevented immunopathology and rescued the mice from mortality. These findings place PKR and the ISR as central components of immunopathology in vivo and identify therapeutic targets for treatment of human diseases associated with the ADAR1-MDA5 axis.

Automated summary

ADAR1 is a negative regulator of the RNA sensor MDA5 and loss of ADAR1 function can cause immune diseases. Research in a mouse model showed that a small-molecule inhibitor targeting the eIF2 alpha kinase PKR and ISR can prevent immunopathology and rescue mice from death. This highlights PKR and ISR as central components of immunopathology and potential therapeutic targets for human diseases associated with the ADAR1-MDA5 axis.