Universität zu Köln

Jiao, Huipeng ORCID: 0000-0001-9632-6176, Wachsmuth, Laurens, Wolf, Simone ORCID: 0000-0003-2073-8312, Lohmann, Juliane, Nagata, Masahiro, Kaya, Goeksu Goekberk, Oikonomou, Nikos, Kondylis, Vangelis ORCID: 0000-0002-6970-8731, Rogg, Manuel ORCID: 0000-0002-6658-9159, Diebold, Martin ORCID: 0000-0001-9636-6936, Troeder, Simon E., Zevnik, Branko, Prinz, Marco, Schell, Christoph ORCID: 0000-0001-5344-624X, Young, George R., Kassiotis, George and Pasparakis, Manolis ORCID: 0000-0002-9870-0966 (2022). ADAR1 averts fatal type I interferon induction by ZBP1. Nature, 607 (7920). S. 776 - 804. BERLIN: NATURE PORTFOLIO. ISSN 1476-4687

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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-Goutieres syndrome and bilateral striatal necrosis(1-3). The IFN-inducible p150 isoform of ADAR1 contains a Z alpha domain that recognizes RNA with an alternative left-handeddouble-helix structure, termed Z-RNA(4,5). Hemizygous ADAR1 mutations in the Z alpha domain cause type I IFN-mediated pathologies in humans(2,3) and mice(6-8); 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 Z alpha domains(9), promotes type I IFN activation and fatal pathology in mice with impaired ADAR1 function. ZBP1 deficiency or mutation of its Z alpha domains reduced the expression of IFN-stimulated genes and largely prevented early postnatal lethality in mice with hemizygous expression of ADAR1 with mutated Z alpha domain (Adar1(mZ alpha/-) mice). Adar1(mZ alpha/-) 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 Adar1(mZ alpha/-) 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Jiao, Huipeng UNSPECIFIED orcid.org/0000-0001-9632-6176 UNSPECIFIED Wachsmuth, Laurens UNSPECIFIED UNSPECIFIED UNSPECIFIED Wolf, Simone UNSPECIFIED orcid.org/0000-0003-2073-8312 UNSPECIFIED Lohmann, Juliane UNSPECIFIED UNSPECIFIED UNSPECIFIED Nagata, Masahiro UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaya, Goeksu Goekberk UNSPECIFIED UNSPECIFIED UNSPECIFIED Oikonomou, Nikos UNSPECIFIED UNSPECIFIED UNSPECIFIED Kondylis, Vangelis UNSPECIFIED orcid.org/0000-0002-6970-8731 UNSPECIFIED Rogg, Manuel UNSPECIFIED orcid.org/0000-0002-6658-9159 UNSPECIFIED Diebold, Martin UNSPECIFIED orcid.org/0000-0001-9636-6936 UNSPECIFIED Troeder, Simon E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zevnik, Branko UNSPECIFIED UNSPECIFIED UNSPECIFIED Prinz, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED Schell, Christoph UNSPECIFIED orcid.org/0000-0001-5344-624X UNSPECIFIED Young, George R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kassiotis, George UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-681082
DOI:	10.1038/s41586-022-04878-9
Journal or Publication Title:	Nature
Volume:	607
Number:	7920
Page Range:	S. 776 - 804
Date:	2022
Publisher:	NATURE PORTFOLIO
Place of Publication:	BERLIN
ISSN:	1476-4687
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DOUBLE-STRANDED-RNA; Z-ALPHA DOMAIN; EDITING ENZYME; Z-DNA; DEAMINASE ADAR1; MUTATIONS; DSRNA; CELL; AUTOIMMUNITY; NECROPTOSIS Multiple languages Multidisciplinary Sciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68108