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

Full text not available from this repository.

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:
CreatorsEmailORCIDORCID Put Code
Jiao, HuipengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wachsmuth, LaurensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kumari, SnehlataUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwarzer, RobinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lin, JuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eren, Remzi OnurUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fisher, AmandaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lane, RebeccaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Young, George R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kassiotis, GeorgeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaiser, William J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pasparakis, ManolisUNSPECIFIEDorcid.org/0000-0002-9870-0966UNSPECIFIED
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: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
Z-DNA; BINDING DOMAIN; RNA; PROTEIN; INHIBITION; NECROSIS; REVEALS; COMPLEX; RIP3Multiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34029

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item