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Yin, C.* ; Fedorov, A.* ; Guo, H.* ; Crawford, J.C.* ; Rousseau, C.* ; Zhong, X.* ; Williams, R.M.* ; Gautam, A.K.* ; Koehler, H.S.* ; Whisnant, A.W.* ; Hennig, T.* ; Rozina, A.* ; Zhong, Y.* ; Lv, S.* ; Bergant, V.* ; Wang, S.* ; Dröge, P.* ; Miller, S.* ; Poptsova, M.* ; Rehwinkel, J.* ; Pichlmair, A. ; Mocarski, E.S.* ; Thomas, P.G.* ; Dölken, L.* ; Zhang, T.* ; Herbert, A.* ; Balachandran, S.*

Host cell Z-RNAs activate ZBP1 during virus infections.

Nature, DOI: 10.1038/s41586-025-09705-5 (2025)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Z-alpha Domain; Z-dna; Protein; Type-1; Necroptosis; Binding; Gene; Transcription; Expression; Sequence
ISSN (print) / ISBN 0028-0836
e-ISSN 1476-4687
Zeitschrift Nature
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Virology (VIRO)
Förderungen NIH Cancer Center Support Grant
UKRI Medical Research Council
The 1.3.5 project for disciplines of excellence from West China Hospital of Sichuan University
National Science and Technology Major Project of China
National Natural Science Foundation of China
Association of Lebanese and Syrian American Charities at St Jude Children's Hospital
St Jude Center of Excellence for Influenza Research and Surveillance (SJCEIRS) NIAID
Slovenian Research and Innovation Agency
European Research Council
Bohringer Ingelheim Funds
Radcliffe Department of Medicine and Keble and St Cross Oxford Colleges
Clarendon Fund
Basic Research Program of the National Research University Higher School of Economics
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)
German Research Foundation (DFG)
Danish National Research Foundation (DNRF)
State of Bavaria
German Research Foundation
NIH grants