Self-RNAs drive activation of innate immunity during RNA virus infection and are regulated by ADAR1 4039

Abstract Description Innate immune sensing of viral double-stranded (ds) RNA induces the transcription of hundreds of interferon stimulated genes (ISGs) that shift the cell into an antiviral state. We have shown that measles virus (MeV) utilizes the 150 kDa isoform of adenosine deaminase acting on RNA 1 (ADAR1-p150) to prevent activation of protein kinase R (PKR), thereby subverting a type-I interferon response. Hypothesizing that cytoplasmic localization of ADAR1-p150 is required for this pro-viral activity, we generated cell lines expressing single isoforms and localization mutants of ADAR1. Based on MeV replication studies in these cells, we concluded that both nuclear and cytoplasmic ADAR1-p150 prevents PKR activation. However, only cytoplasmic but not nuclear ADAR1-p110 can efficiently prevent PKR activation. These observations suggest a bimodal activation of IFN responses. Initial sensing of viral dsRNA leads to upregulation of a subset of ISGs forming p150-specific self-RNA substrates driving PKR activation. Through ADAR editome analyses, we have identified candidate p150- and p110-specific self-RNA substrates that may be the drivers of this positive feedback loop. RNA immunoprecipitation studies to identify the specific substrates of ADAR1-p150 and PKR during MeV infection are underway to strengthen this novel model of a positive feedback loop driven by self-RNAs. Altogether, our findings shift the paradigm on the regulatory properties of self-RNA on amplifying antiviral innate immunity. Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)