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The role of RNA editing by ADAR1 in prevention of innate immune sensing of self-RNA

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Abstract

The innate immune system is the first line of the cellular defence against invading pathogens. A critical component of this defence is the capacity to discriminate foreign RNA molecules, which are distinct from most cellular RNAs in structure and/or modifications. However, a series of rare autoimmune/autoinflammatory diseases in humans highlight the propensity for the innate immune sensing system to be activated by endogenous cellular double-stranded RNAs (dsRNAs), underscoring the fine line between distinguishing self from non-self. The RNA editing enzyme ADAR1 has recently emerged as a key regulator that prevents innate immune pathway activation, principally the cytosolic dsRNA sensor MDA5, from inducing interferon in response to double-stranded RNA structures within endogenous RNAs. Adenosine-to-Inosine RNA editing by ADAR1 is proposed to destabilise duplexes formed from inverted repetitive elements within RNAs, which appear to prevent MDA5 from sensing these RNA as virus-like in the cytoplasm. Aberrant activation of these pathways has catastrophic effects at both a cellular and organismal level, contributing to one of the causes of the conditions collectively known as the type I interferonopathies.

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Acknowledgements

Work in the laboratory was/is supported by The Leukaemia Foundation (CRW); NHMRC Project Grant (CRW; APP1021216 and APP1102006), NHMRC Career Development Award (CRW; APP559016); in part by the Victorian State Government’s OIS Program (to St. Vincent’s Institute); CRW was the Leukaemia Foundation Phillip Desbrow Senior Research Fellow.

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Authors and Affiliations

  1. St. Vincent’s Institute of Medical Research, 9 Princes St, Fitzroy, 3065, Victoria, Australia

    Jacki E. Heraud-Farlow & Carl R. Walkley

  2. Department of Medicine, St. Vincent’s Hospital, University of Melbourne, Fitzroy, 3065, Victoria, Australia

    Carl R. Walkley

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  1. Jacki E. Heraud-Farlow
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Correspondence to Carl R. Walkley.

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J.E.H-F. and C.R.W. analysed and interpreted data, provided intellectual input and wrote the manuscript.

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The funders of our work had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. All authors declare no conflicts of interest.

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Heraud-Farlow, J.E., Walkley, C.R. The role of RNA editing by ADAR1 in prevention of innate immune sensing of self-RNA. J Mol Med 94, 1095–1102 (2016). https://doi.org/10.1007/s00109-016-1416-1

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