RNA binding by ADARs prevents RNA interference from attacking self-produced dsRNA

Abstract

The ability of an organism to distinguish between self and foreign double-stranded RNA (dsRNA) is central to eliciting an immune response when needed while preventing autoimmunity. Using Caenorhabditis elegans, we investigated the interplay between two host pathways that regulate dsRNA expression and function, adenosine-to-inosine RNA editing by adenosine deaminases that act on RNA (ADARs), and RNA interference (RNAi). We found that the number of small interfering RNAs (siRNAs) targeting edited genes is significantly up-regulated in ADAR mutant animals. In addition, despite an almost complete depletion of primary siRNAs generated from editing sites in wild-type animals, secondary siRNAs are generated from edited transcripts, suggesting that ADARs antagonize only the first step of RNAi processing. We show that ADARs interfere with the efficacy of exogenous RNAi in vivo, likely to prevent trans-silencing, and provide evidence that ADR-2 binding to dsRNA is required for efficient RNAi suppression. This work sheds light on how RNA editing safeguards self-dsRNAs against immune recognition and by-product degradation.