ADAR1 averts fatal type I interferon induction by ZBP1

Huipeng Jiao, Laurens Wachsmuth, Simone Wolf, Juliane Lohmann, Masahiro Nagata, Göksu Gökberk Kaya, Nikos Oikonomou, Vangelis Kondylis, Manuel Rogg, Martin Diebold, Simon E. Tröder, Branko Zevnik, Marco Prinz, Christoph Schell, George R. Young, George Kassiotis and Manolis Pasparakis ()
Additional contact information
Huipeng Jiao: University of Cologne
Laurens Wachsmuth: University of Cologne
Simone Wolf: University of Cologne
Juliane Lohmann: University of Cologne
Masahiro Nagata: University of Cologne
Göksu Gökberk Kaya: University of Cologne
Nikos Oikonomou: University of Cologne
Vangelis Kondylis: University of Cologne
Manuel Rogg: Medical Center–University of Freiburg
Martin Diebold: University of Freiburg
Simon E. Tröder: University of Cologne
Branko Zevnik: University of Cologne
Marco Prinz: University of Freiburg
Christoph Schell: Medical Center–University of Freiburg
George R. Young: Bioinformatics and Biostatistics STP
George Kassiotis: The Francis Crick Institute
Manolis Pasparakis: University of Cologne

Nature, 2022, vol. 607, issue 7920, 776-783

Abstract: Abstract Mutations of the ADAR1 gene encoding an RNA deaminase cause severe diseases associated with chronic activation of type I interferon (IFN) responses, including Aicardi–Goutières syndrome and bilateral striatal necrosis1–3. The IFN-inducible p150 isoform of ADAR1 contains a Zα domain that recognizes RNA with an alternative left-handed double-helix structure, termed Z-RNA4,5. Hemizygous ADAR1 mutations in the Zα domain cause type I IFN-mediated pathologies in humans2,3 and mice6–8; however, it remains unclear how the interaction of ADAR1 with Z-RNA prevents IFN activation. Here we show that Z-DNA-binding protein 1 (ZBP1), the only other protein in mammals known to harbour Zα domains9, promotes type I IFN activation and fatal pathology in mice with impaired ADAR1 function. ZBP1 deficiency or mutation of its Zα domains reduced the expression of IFN-stimulated genes and largely prevented early postnatal lethality in mice with hemizygous expression of ADAR1 with mutated Zα domain (Adar1mZα/– mice). Adar1mZα/– mice showed upregulation and impaired editing of endogenous retroelement-derived complementary RNA reads, which represent a likely source of Z-RNAs activating ZBP1. Notably, ZBP1 promoted IFN activation and severe pathology in Adar1mZα/– mice in a manner independent of RIPK1, RIPK3, MLKL-mediated necroptosis and caspase-8-dependent apoptosis, suggesting a novel mechanism of action. Thus, ADAR1 prevents endogenous Z-RNA-dependent activation of pathogenic type I IFN responses by ZBP1, suggesting that ZBP1 could contribute to type I interferonopathies caused by ADAR1 mutations.

Date: 2022
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DOI: 10.1038/s41586-022-04878-9

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