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

• Published in: Immunity (Cambridge, Mass.) Mass.), 2021-09, Vol.54 (9), p.1948-1960.e5
• Main Authors: Maurano, Megan, Snyder, Jessica M., Connelly, Caitlin, Henao-Mejia, Jorge, Sidrauski, Carmela, Stetson, Daniel B.
• Format: Article
• Language: English
• Subjects: ADAR1; Aicardi-Goutières syndrome; integrated stress response; interferons; LGP2; MDA5; PKR
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2021.07.001

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-Goutières 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 eIF2α kinase PKR. A small-molecule inhibitor of the integrated stress response (ISR) that acts downstream of eIF2α 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. [Display omitted] •AdarP195A/p150- mice model ADAR1 mutations found in human Aicardi-Goutières syndrome•Disease in AdarP195A/p150- mice requires MDA5, LGP2, the type I IFN receptor, and PKR•AdarP195A/p150- mice develop PKR-dependent activation of integrated stress response (ISR)•Pharmacological inhibition of the ISR in vivo prevents all aspects of disease Mutations in ADAR1 cause human immune diseases, including Aicardi-Goutières syndrome (AGS), but the mechanisms of disease pathogenesis remain unknown. Using a mouse model of ADAR1 mutation, Maurano et al. define a pathway linking MDA5 and LGP2 to PKR and the integrated stress response (ISR). Pharmacological inhibition of the ISR prevents disease, establishing its role in immunopathology caused by ADAR1 mutations.