Protein Kinase R and the Integrated Stress Response Drive Immunopathology Caused by Mutations in the RNA Deaminase ADAR1

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2021 Aug 3

PMID 34343497

Citations 52

Authors

Megan Maurano

Jessica M Snyder

Caitlin Connelly

Jorge Henao-Mejia

Carmela Sidrauski

Daniel B Stetson

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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