ADAR1 editing is necessary for only a small subset of cytosolic dsRNAs to evade MDA5-mediated autoimmunity
Tao Sun, Qin Li, Jonathan M. Geisinger, Shi-Bin Hu, Boming Fan, Shichen Su, Waitang Tsui, Hongchao Guo, Jinbiao Ma, Jin Billy Li
Abstract
Endogenous long double-stranded RNAs (dsRNAs), which are not edited by the RNA editing enzyme ADAR1, may activate the antiviral dsRNA receptor MDA5 to trigger interferon-mediated immune responses. Among the large number of endogenous long dsRNAs, the key substrates that activate MDA5—termed as immunogenic dsRNAs—remain largely unidentified. Here we reveal that human immunogenic dsRNAs constitute a surprisingly small fraction of all cellular dsRNAs. We found that these immunogenic dsRNAs were highly enriched in mRNAs and depleted of introns, consistent with their role as cytosolic MDA5 substrates. We validated the MDA5-dependent immunogenicity of these dsRNAs, which was dampened following ADAR1-mediated RNA editing. Notably, immunogenic dsRNAs were enriched at genetic susceptibility loci associated with common inflammatory diseases, implying their functional importance. We anticipate that a focused analysis of immunogenic dsRNAs will enhance our understanding and treatment of cancer and inflammatory diseases, where the roles of dsRNA editing and sensing are increasingly recognized. The authors show that only a small subset of cytosolic double-stranded RNAs (dsRNAs) requires ADAR1-mediated RNA editing to evade an MDA5-dependent immune response. These immunogenic dsRNAs are enriched in mRNAs and overlap with GWAS signals for common inflammatory diseases.