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Recognition of Z-RNA by ADAR1 limits interferon responses

Qiannan Tang, Rachel E. Rigby, George R. Young, Astrid Korning-Hvidt, Tiong Kit Tan, Anne Bridgeman, Alain R. Townsend, George Kassiotis, View ORCID ProfileJan Rehwinkel
doi: https://doi.org/10.1101/2020.12.04.411793
Qiannan Tang
1Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK
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Rachel E. Rigby
1Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK
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George R. Young
2Retrovirus–Host Interactions, The Francis Crick Institute, London, UK
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Astrid Korning-Hvidt
1Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK
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Tiong Kit Tan
1Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK
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Anne Bridgeman
1Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK
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Alain R. Townsend
1Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK
3Centre for Translational Immunology, Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK
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George Kassiotis
4Retroviral Immunology, The Francis Crick Institute, London, UK
5Department of Infectious Disease, Faculty of Medicine, Imperial College London, London, UK
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Jan Rehwinkel
1Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK
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  • ORCID record for Jan Rehwinkel
  • For correspondence: jan.rehwinkel@imm.ox.ac.uk
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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 (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 Adar1mZα/mZα mice. Concomitantly, Adar1mZα/mZα mice showed improved control of influenza A virus. The spontaneous IFN response in Adar1mZα/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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted December 04, 2020.
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Recognition of Z-RNA by ADAR1 limits interferon responses
Qiannan Tang, Rachel E. Rigby, George R. Young, Astrid Korning-Hvidt, Tiong Kit Tan, Anne Bridgeman, Alain R. Townsend, George Kassiotis, Jan Rehwinkel
bioRxiv 2020.12.04.411793; doi: https://doi.org/10.1101/2020.12.04.411793
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Recognition of Z-RNA by ADAR1 limits interferon responses
Qiannan Tang, Rachel E. Rigby, George R. Young, Astrid Korning-Hvidt, Tiong Kit Tan, Anne Bridgeman, Alain R. Townsend, George Kassiotis, Jan Rehwinkel
bioRxiv 2020.12.04.411793; doi: https://doi.org/10.1101/2020.12.04.411793

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