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Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation 期刊论文
NATURE, 2020, 580 (7803) : 391-+
作者:  Zhang, Zhibin;  Zhang, Ying;  Xia, Shiyu;  Kong, Qing;  Li, Shunying;  Liu, Xing;  Junqueira, Caroline;  Meza-Sosa, Karla F.;  Mok, Temy Mo Yin;  Ansara, James;  Sengupta, Satyaki;  Yao, Yandan;  Wu, Hao;  Lieberman, Judy
收藏  |  浏览/下载：10/0  |  提交时间：2020/07/03

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).


  
Structures and gating mechanism of human TRPM2 期刊论文
SCIENCE, 2018, 362 (6421) : 1377-+
作者:  Wang, Longfei;  Fu, Tian-Min;  Zhou, Yiming;  Xia, Shiyu;  Greka, Anna;  Wu, Hao
收藏  |  浏览/下载：13/0  |  提交时间：2019/11/27
Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death 期刊论文
SCIENCE, 2018, 362 (6418) : 1064-+
作者:  Orning, Pontus;  Weng, Dan;  Starheim, Kristian;  Ratner, Dmitry;  Best, Zachary;  Lee, Bettina;  Brooks, Alexandria;  Xia, Shiyu;  Wu, Hao;  Kelliher, Michelle A.;  Berger, Scott B.;  Gough, Peter J.;  Bertin, John;  Proulx, Megan M.;  Goguen, Jon D.;  Kayagaki, Nobuhiko;  Fitzgerald, Katherine A.;  Lien, Egil
收藏  |  浏览/下载：11/0  |  提交时间：2019/11/27