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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)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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
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)