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Host cell Z-RNAs activate ZBP1 during virus infections

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作者：
Chaoran Yin[1] * ; Aleksandr Fedorov[2,3] * ; Hongyan Guo[4] * ; Jeremy Chase Crawford[5] ; Claire Rousseau[6,7] ; Xiao Zhong[8] ; Riley M. Williams[1] ; Avishekh Gautam[1] ; Heather S. Koehler[9] ; Adam W. Whisnant[6,7] ; Thomas Hennig[6,7] ; Anna Rozina[3] ; Yuhan Zhong[8] ; Shuangjuan Lv[8] ; Valter Bergant[10] ; [11] ; Shuqi Wang[4] ; Peter Dröge[12] ; Sven Miller[1] ; Maria Poptsova[2] ; Jan Rehwinkel[3] ; Andreas Pichlmair[10,13,14] ; Edward S. Mocarski[15] ; Paul G. Thomas[5] ; Lars Dölken[6,7,16,17] ; Ting Zhang[8,18,19] ; Alan Herbert[2,20] ; Siddharth Balachandran[1] ;
机构： [1]Center for Immunology, Fox Chase Cancer Center, Philadelphia, PA, USA [2]Laboratory of Bioinformatics, Faculty of Computer Science, National Research University Higher School of Economics, 11 Pokrovsky Bulvar, Moscow, Russia 101000 [3]Medical Research Council Translational Immune Discovery Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK [4]Department of Microbiology and Immunology, Louisiana State University Health Shreveport, Shreveport, LA 71103, U.S.A. [5]Department of Host-Microbe Interactions, St. Jude Children’s Research Hospital, Memphis, TN, U.S.A. [6]Institute for Virology and Immunobiology, Julius-Maximilians-Universität-Würzburg, Würzburg, Germany [7]Institute of Virology, Hannover Medical School, Carl Neuberg Strasse 1, 30625 Hannover, Germany [8]Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, People’s Republic of China [9]School of Molecular Biosciences, Washington State University, Pullman, WA, U.S.A. [10]Technical University of Munich, School of Medicine & Health, Institute of Virology, Munich, Germany [11]National Institute of Chemistry, Ljubljana, Slovenia [12]School of Biological Sciences, Nanyang Technological University, 637551 Singapore, Singapore [13]Systems Virology, Helmholtz Center Munich, Munich, Germany [14]German Centre for Infection Research (DZIF), Partner site Munich, Germany [15]Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, U.S.A. [16]Helmholtz Institute for RNA-based Infection Research (HIRI), Würzburg, Germany. [17]Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany [18]Department of General Surgery, West China Hospital, Sichuan University, Chengdu, People’s Republic of China. [19]Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China. [20]InsideOutBio, 42 8th Street, Charlestown, MA, U.S.A
出处：
DOI： 10.1038/s41586-025-09705-5
ISSN：

关键词： Necroptosis HSV-1 IAV Zα Z-RNA Z-DNA dsRNA ZBP1 RIPK3 MLKL DoTT Flipons

摘要：
Herpes simplex virus 1 (HSV-1) and Influenza A viruses (IAV) induce Z-form nucleic acid Binding Protein 1 (ZBP1)-initiated cell death1-8. ZBP1 is activated by Z-RNA1,7,9, and the Z-RNAs which trigger ZBP1 during HSV-1 and IAV infections were assumed to be of viral origin1. However, we show here that host cell-encoded Z-RNAs are major and sufficient ZBP1 activating ligands following infection by these two human pathogens. The majority of cellular Z-RNAs mapped to intergenic endogenous retroelements (EREs) embedded within abnormally long 3' extensions of host cell mRNAs. These aberrant host cell transcripts arose as a consequence of Disruption of Transcription Termination (DoTT), a virus-driven phenomenon which disables Cleavage and Polyadenylation Specificity Factor (CPSF)-mediated 3' processing of nascent pre-mRNAs10-15. Mutant viruses lacking ICP27 or NS1, the virus-encoded proteins responsible for inhibiting CPSF and triggering DoTT13,15, failed to induce host cell Z-RNA accrual and were attenuated in their ability to stimulate ZBP1. Ectopic expression of HSV-1 ICP27 or IAV NS1, or pharmacological blockade of CPSF activity, induced accumulation of host cell Z-RNAs and activated ZBP1. These results demonstrate that DoTT-generated cellular Z-RNAs are bona fide ZBP1 ligands, and position ZBP1-activated cell death as a host response to counter viral disruption of the cellular transcriptional machinery.© 2025. The Author(s), under exclusive licence to Springer Nature Limited.

基金：
This work was supported by NIH grants AI135025,AI144400, AI161624, and CA168621 to S.B., NIH grant R21AI175590 and COBRE P20GM134974 to H.G., R21CA303392 to H.G. and S.B., NIH grant R01 AI121832 and the St. Jude Center of Excellence for Influenza Research and Surveillance (SJCEIRS) NIAID contract HHSN272201400006C to P.G.T., funding from the Association of Lebanese and Syrian American Charities at St. Jude Children’s Hospital to J.C.C., and P.G.T.. T.Z was supported by Grant 32370157 from the National Natural Science Foundation of China, the National Science and Technology Major Project of China (2023ZD0500502) and 1.3.5 project for disciplines of excellence from West China Hospital of Sichuan University（ZYYC24008). J.R. acknowledges funding from UKRI Medical Research Council, grant number MR/Y013212/1. V.B. acknowledges support by the Slovenian Research and Innovation Agency (P1-0242, J4-60082). A.P. was supported by the European Research Council (ERC-CoG- 817798-ProDAP), the German Research Foundation (CRC-TRR179/TP24, CRC-TRR237/A07, CRC-TRR353/B04), the State of Bavaria (“P3M” - BayVFP 2024-2027) and the Danish National Research Foundation (DNRF 164; CiViA). L.D. was supported by the European Research Council (ERC-2021-CoG-101041177- DecipherHSV), the German Research Foundation (DFG) – SFB 1583/1 – project number: 492620490 and funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy - EXC 2155 - project number 390874280. A. F. and M. P. were supported by the Basic Research Program of the National Research University Higher School of Economics, for which A. H. is an International Supervisor. A.F. and A.R. acknowledge funding from the Clarendon Fund, the Radcliffe Department of Medicine, and Keble and St. Cross Oxford Colleges. Additional funds were provided by Boehringer Ingelheim Funds to A.R. and NIH Cancer Center Support Grant P30CA006927 to S.B
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外文
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出版当年[2025]版：
大类 | 1 区 综合性期刊
小类 | 1 区 综合性期刊
最新[2025]版：
大类 | 1 区 综合性期刊
小类 | 1 区 综合性期刊
第一作者：
第一作者机构： [1]Center for Immunology, Fox Chase Cancer Center, Philadelphia, PA, USA
共同第一作者：
通讯作者：
通讯机构： [2]Laboratory of Bioinformatics, Faculty of Computer Science, National Research University Higher School of Economics, 11 Pokrovsky Bulvar, Moscow, Russia 101000 [6]Institute for Virology and Immunobiology, Julius-Maximilians-Universität-Würzburg, Würzburg, Germany [7]Institute of Virology, Hannover Medical School, Carl Neuberg Strasse 1, 30625 Hannover, Germany [8]Laboratory of Hepatic AI Translation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, People’s Republic of China [16]Helmholtz Institute for RNA-based Infection Research (HIRI), Würzburg, Germany. [17]Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany [18]Department of General Surgery, West China Hospital, Sichuan University, Chengdu, People’s Republic of China. [19]Liver Transplant Center, Transplant Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China. [20]InsideOutBio, 42 8th Street, Charlestown, MA, U.S.A
推荐引用方式(GB/T 7714)：
Chaoran Yin,Aleksandr Fedorov,Hongyan Guo,et al.Host cell Z-RNAs activate ZBP1 during virus infections[J].Nature.2025,doi:10.1038/s41586-025-09705-5.
APA：
Chaoran Yin,Aleksandr Fedorov,Hongyan Guo,Jeremy Chase Crawford,Claire Rousseau...&Siddharth Balachandran.(2025).Host cell Z-RNAs activate ZBP1 during virus infections.Nature,,
MLA：
Chaoran Yin,et al."Host cell Z-RNAs activate ZBP1 during virus infections".Nature .(2025)

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