ADAR1 averts fatal type I interferon induction by ZBP1

Autor: 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, Manolis Pasparakis
Rok vydání: 2022
Předmět:
Zdroj: Nature. 607:776-783
ISSN: 1476-4687
0028-0836
Popis: Mutations of theADAR1gene 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. HemizygousADAR1mutations 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 inAdar1mZα/–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 byADAR1mutations.
Databáze: OpenAIRE
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