Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation

Huipeng Jiao, Laurens Wachsmuth, Snehlata Kumari, Robin Schwarzer, Juan Lin, Remzi Onur Eren, Amanda Fisher, Rebecca Lane, George R. Young, George Kassiotis, William J. Kaiser and Manolis Pasparakis ()
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Huipeng Jiao: University of Cologne
Laurens Wachsmuth: University of Cologne
Snehlata Kumari: University of Cologne
Robin Schwarzer: University of Cologne
Juan Lin: University of Cologne
Remzi Onur Eren: University of Cologne
Amanda Fisher: University of Texas Health Science Center
Rebecca Lane: University of Texas Health Science Center
George R. Young: The Francis Crick Institute
George Kassiotis: The Francis Crick Institute
William J. Kaiser: University of Texas Health Science Center
Manolis Pasparakis: University of Cologne

Nature, 2020, vol. 580, issue 7803, 391-395

Abstract: Abstract The biological function of Z-DNA and Z-RNA, nucleic acid structures with a left-handed double helix, is poorly understood1–3. Z-DNA-binding protein 1 (ZBP1; also known as DAI or DLM-1) is a nucleic acid sensor that contains two Zα domains that bind Z-DNA4,5 and Z-RNA6–8. ZBP1 mediates host defence against some viruses6,7,9–14 by sensing viral nucleic acids6,7,10. RIPK1 deficiency, or mutation of its RIP homotypic interaction motif (RHIM), triggers ZBP1-dependent necroptosis and inflammation in mice15,16. However, the mechanisms that induce ZBP1 activation in the absence of viral infection remain unknown. Here we show that Zα-dependent sensing of endogenous ligands induces ZBP1-mediated perinatal lethality in mice expressing RIPK1 with mutated RHIM (Ripk1mR/mR), skin inflammation in mice with epidermis-specific RIPK1 deficiency (RIPK1E-KO) and colitis in mice with intestinal epithelial-specific FADD deficiency (FADDIEC-KO). Consistently, functional Zα 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 Zα-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 Zα-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 Zα-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 CASP817–20.

Date: 2020
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DOI: 10.1038/s41586-020-2129-8

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