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ADAR1 averts fatal type I interferon induction by ZBP1
- 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