Universität zu Köln

Jiao, Huipeng, Wachsmuth, Laurens, Kumari, Snehlata, Schwarzer, Robin, Lin, Juan, Eren, Remzi Onur, Fisher, Amanda, Lane, Rebecca, Young, George R., Kassiotis, George, Kaiser, William J. and Pasparakis, Manolis ORCID: 0000-0002-9870-0966 (2020). Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation. Nature, 580 (7803). S. 391 - 410. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-4687

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Abstract

Analyses of mouse models of inflammation suggest some chronic inflammatory conditions may result from Z-DNA-binding protein 1 sensing endogenous Z-form nucleic acids-such as those of endogenous retroelements-through its Z alpha domains. The biological function of Z-DNA and Z-RNA, nucleic acid structures with a left-handed double helix, is poorly understood(1-3). Z-DNA-binding protein 1 (ZBP1; also known as DAI or DLM-1) is a nucleic acid sensor that contains two Z alpha domains that bind Z-DNA(4,5) and Z-RNA(6-8). ZBP1 mediates host defence against some viruses(6,7,9-14) by sensing viral nucleic acids(6,7,10). RIPK1 deficiency, or mutation of its RIP homotypic interaction motif (RHIM), triggers ZBP1-dependent necroptosis and inflammation in mice(15,16). However, the mechanisms that induce ZBP1 activation in the absence of viral infection remain unknown. Here we show that Z alpha-dependent sensing of endogenous ligands induces ZBP1-mediated perinatal lethality in mice expressing RIPK1 with mutated RHIM (Ripk1(mR/mR)), skin inflammation in mice with epidermis-specific RIPK1 deficiency (RIPK1(E-KO)) and colitis in mice with intestinal epithelial-specific FADD deficiency (FADD(IEC-KO)). Consistently, functional Z alpha domains were required for ZBP1-induced necroptosis in fibroblasts that were treated with caspase inhibitors or express RIPK1 with mutated RHIM. Inhibition of nuclear export triggered the Z alpha-dependent activation of RIPK3 in the nucleus resulting in cell death, which suggests that ZBP1 may recognize nuclear Z-form nucleic acids. We found that ZBP1 constitutively bound cellular double-stranded RNA in a Z alpha-dependent manner. Complementary reads derived from endogenous retroelements were detected in epidermal RNA, which suggests that double-stranded RNA derived from these retroelements may act as a Z alpha-domain ligand that triggers the activation of ZBP1. Collectively, our results provide evidence that the sensing of endogenous Z-form nucleic acids by ZBP1 triggers RIPK3-dependent necroptosis and inflammation, which could underlie the development of chronic inflammatory conditions-particularly in individuals with mutations in RIPK1 and CASP8(17-20).

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Jiao, Huipeng UNSPECIFIED UNSPECIFIED UNSPECIFIED Wachsmuth, Laurens UNSPECIFIED UNSPECIFIED UNSPECIFIED Kumari, Snehlata UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwarzer, Robin UNSPECIFIED UNSPECIFIED UNSPECIFIED Lin, Juan UNSPECIFIED UNSPECIFIED UNSPECIFIED Eren, Remzi Onur UNSPECIFIED UNSPECIFIED UNSPECIFIED Fisher, Amanda UNSPECIFIED UNSPECIFIED UNSPECIFIED Lane, Rebecca UNSPECIFIED UNSPECIFIED UNSPECIFIED Young, George R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kassiotis, George UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaiser, William J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-340296
DOI:	10.1038/s41586-020-2129-8
Journal or Publication Title:	Nature
Volume:	580
Number:	7803
Page Range:	S. 391 - 410
Date:	2020
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-4687
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Institute for Genetics
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language Z-DNA; BINDING DOMAIN; RNA; PROTEIN; INHIBITION; NECROSIS; REVEALS; COMPLEX; RIP3 Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/34029