ADAR1 limits stress granule formation through both translation-dependent and translation-independent mechanisms

Abstract

ABSTRACT Stress granules (SGs) are cytoplasmic assemblies of RNA and protein that form when translation is repressed during the integrated stress response. SGs assemble from the combination of RNA–RNA, RNA–protein and protein–protein interactions between messenger ribonucleoprotein complexes (mRNPs). The protein adenosine deaminase acting on RNA 1 (ADAR1, also known as ADAR) recognizes and modifies double-stranded RNAs (dsRNAs) within cells to prevent an aberrant innate immune response. ADAR1 localizes to SGs, and since RNA–RNA interactions contribute to SG assembly and dsRNA induces SGs, we examined how ADAR1 affects SG formation. First, we demonstrate that ADAR1 depletion triggers SGs by allowing endogenous dsRNA to activate the integrated stress response through activation of PKR (also known as EIF2AK2) and translation repression. However, we also show that ADAR1 limits SG formation independently of translation inhibition. ADAR1 repression of SGs is independent of deaminase activity but is dependent on dsRNA-binding activity, suggesting a model where ADAR1 binding limits RNA–RNA and/or RNA–protein interactions necessary for recruitment to SGs. Given that ADAR1 expression is induced during viral infection, these findings have implications for the role of ADAR1 in the antiviral response. This article has an associated First Person interview with the first author of the paper.