期刊
NATURE
卷 580, 期 7803, 页码 391-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41586-020-2129-8
关键词
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资金
- European Research Council [787826]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [SFB829, 73111208, SFB1218, 269925409, SFB1399, 413326622, SFB1403, 414786233, PA 1476/8-1, 411102043, 390661388]
- Federal Ministry of Education and Research (BMBF, e:med project InCa) [01ZX1901A]
- Francis Crick Institute [FC001099]
- Wellcome Trust [102898/B/13/Z]
- Alexander von Humboldt Foundation
- European Research Council (ERC) [787826] Funding Source: European Research Council (ERC)
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).
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