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<jats:title>Abstract</jats:title><jats:p>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 (Z<jats:italic>α</jats:italic>) domain. We report that knock-in mice bearing two point mutations in the Z<jats:italic>α</jats:italic> 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 <jats:italic>Adar1<jats:sup>mZα/mZα</jats:sup></jats:italic> mice. Concomitantly, <jats:italic>Adar1<jats:sup>mZα/mZα</jats:sup></jats:italic> mice showed improved control of influenza A virus. The spontaneous IFN response in <jats:italic>Adar1<jats:sup>mZα/mZα</jats:sup></jats:italic> mice required MAVS, implicating cytosolic RNA sensing. Finally, analysis of A-to-I changes revealed a specific requirement of ADAR1’s Z<jats:italic>α</jats:italic> 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.</jats:p>

Original publication

DOI

10.1101/2020.12.04.411793

Type

Journal article

Publisher

Cold Spring Harbor Laboratory

Publication Date

05/12/2020