Recognition of Z-RNA by ADAR1 limits interferon responses

Abstract

Nucleic acids are powerful triggers of innate immunity and can adopt the unusual Z-conformation. The p150 isoform of adenosine deaminase acting on RNA 1 (ADAR1) prevents aberrant interferon (IFN) induction and contains a Z-nucleic acid binding (Zα) domain. We report that knock-in mice bearing two point mutations in the Zα domain of ADAR1, which abolish binding to Z-form nucleic acids, spontaneously induced type I IFNs and IFN-stimulated genes (ISGs) in multiple organs. This included the lung where both stromal and haematopoietic cells displayed ISG induction in Adar1^mZα/mZα mice. Concomitantly, Adar1^mZα/mZα mice showed improved control of influenza A virus. The spontaneous IFN response in Adar1^mZα/mZα mice required MAVS, implicating cytosolic RNA sensing. Finally, analysis of A-to-I changes revealed a specific requirement of ADAR1’s Zα domain in editing of a subset of RNAs. In summary, our results reveal that endogenous RNAs in Z-conformation have immunostimulatory potential that is curtailed by ADAR1.