Recognition of Z-RNA by ADAR1 limits interferon responses

Tang, Q.; Rigby, R. E.; Young, G. R.; Korning-Hvidt, A.; Tang, T. K.; Bridgeman, A.; Townsend, A. R.; Kassiotis, G.; Rehwinkel, J.

doi:10.1101/2020.12.04.411793

bioRxiv · 10.1101/2020.12.04.411793

Recognition of Z-RNA by ADAR1 limits interferon responses

Tang, Q.·Rigby, R. E.·Young, G. R.·Korning-Hvidt, A.·Tang, T. K.·Bridgeman, A.·Townsend, A. R.·Kassiotis, G.·Rehwinkel, J.

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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 (Z) domain. We report that knock-in mice bearing two point mutations in the Z 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 Adar1mZ/mZ mice. Concomitantly, Adar1mZ/mZ mice showed improved control of influenza A virus. The spontaneous IFN response in Adar1mZ/mZ mice required MAVS, implicating cytosolic RNA sensing. Finally, analysis of A-to-I changes revealed a specific requirement of ADAR1s Z 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.

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Tang, Q., Rigby, R. E., Young, G. R., Korning-Hvidt, A., Tang, T. K., Bridgeman, A., Townsend, A. R., Kassiotis, G., Rehwinkel, J.. 2020-12-04. Recognition of Z-RNA by ADAR1 limits interferon responses. https://doi.org/10.1101/2020.12.04.411793

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