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ADAR1 averts fatal type I interferon induction by ZBP1

Authors :
Jiao, Huipeng
Wachsmuth, Laurens
Wolf, Simone
Lohmann, Juliane
Nagata, Masahiro
Kaya, Göksu Gökberk
Oikonomou, Nikos
Kondylis, Vangelis
Rogg, Manuel
Diebold, Martin
Tröder, Simon E.
Zevnik, Branko
Prinz, Marco
Schell, Christoph
Young, George R.
Kassiotis, George
Pasparakis, Manolis
Source :
Nature; July 2022, Vol. 607 Issue: 7920 p776-783, 8p
Publication Year :
2022

Abstract

Mutations of the ADAR1gene 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 ADAR1mutations in the Zα domain cause type I IFN-mediated pathologies in humans2,3and 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 ADAR1mutations.

Details

Language :
English
ISSN :
00280836 and 14764687
Volume :
607
Issue :
7920
Database :
Supplemental Index
Journal :
Nature
Publication Type :
Periodical
Accession number :
ejs60396674
Full Text :
https://doi.org/10.1038/s41586-022-04878-9