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

• Published in: Nature (London) Vol. 580; no. 7803; pp. 391 - 395
• Main Authors: 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., Pasparakis, Manolis
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2020; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/2; 13/21; 13/51; 13/95; 14/19; 14/63; 38/39; 38/91; 42; 42/41; 631/250/1933; 631/250/256/2515; 631/45/500; 631/80/304; 64/110; 82/29; Activation; Active Transport, Cell Nucleus; Age; Animals; Antisense nucleic acids; Apoptosis; Binding proteins; Biological research; Biology, Experimental; Caspase; Caspase 8 - metabolism; Caspase inhibitors; Causes of; Cell death; Colitis; Control; Deoxyribonucleic acid; Detection; DNA; DNA structure; DNA-binding protein; Domains; Double-stranded RNA; Epidermis; FADD protein; Female; Fibroblasts; Genetic aspects; Handedness; Humanities and Social Sciences; Hyperplasia; Infections; Inflammation; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Inflammatory bowel disease; Influenza; Intestine; Keratin; Lethality; Ligands; Male; Mice; Mice, Inbred C57BL; multidisciplinary; Mutation; Necroptosis; Necrosis; Nuclear transport; Nuclei (cytology); Nucleic acids; Nucleic Acids - metabolism; Phosphorylation; Physiological aspects; Proteins; Receptor-Interacting Protein Serine-Threonine Kinases - genetics; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Ribonucleic acid; RNA; RNA, Double-Stranded - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Science; Science (multidisciplinary); Skin Diseases - genetics; Skin Diseases - metabolism; Skin Diseases - pathology; Viral infections; Z-form; Germany
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-020-2129-8

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 Zα 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 Zα-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 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 CASP8 17 – 20 . 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 Zα domains.