美国福克斯大通癌症中心Siddharth Balachandran小组取得一项新突破。他们的研究显示，宿主细胞Z-RNAs在病毒感染期间激活ZBP1。相关论文于2025年10月13日发表于国际顶尖学术期刊《自然》杂志上。

然而，研究人员在这里表明，宿主细胞编码的Z-RNAs是感染这两种人类病原体后主要和充分的ZBP1激活配体。大多数细胞Z-RNAs定位于嵌入宿主细胞mRNAs异常长3'延伸的基因间内源性逆转录因子（EREs）。这些异常的宿主细胞转录是转录终止中断（DoTT）的结果，这是一种病毒驱动的现象，它使新生的pre-mRNAs的切割和聚腺苷化特异性因子（CPSF）介导的3'加工失效。突变病毒主题缺乏ICP27或NS1（病毒编码的负责抑制CPSF和触发DoTT的蛋白），无法诱导宿主细胞Z-RNA积累，并且刺激ZBP1的能力减弱。异位表达HSV-1 ICP27或IAV NS1，或药理阻断CPSF活性，诱导宿主细胞Z-RNAs积累，激活ZBP1。这些结果表明，DoTT产生的细胞Z-RNAs是真正的ZBP1配体，并将ZBP1激活的细胞死亡定位为宿主对病毒破坏细胞转录机制的反应。

据了解，单纯疱疹病毒1（HSV-1）和甲型流感病毒主题（IAV）诱导Z型核酸结合蛋白1 （ZBP1）启动细胞死亡。ZBP1被Z-RNA激活，在HSV-1和IAV感染期间触发ZBP1的Z-RNAs被认为是病毒源的。

附：英文原文

Title: Host cell Z-RNAs activate ZBP1 during virus infections

Author: Yin, Chaoran, Fedorov, Aleksandr, Guo, Hongyan, Crawford, Jeremy Chase, Rousseau, Claire, Zhong, Xiao, Williams, Riley M., Gautam, Avishekh, Koehler, Heather S., Whisnant, Adam W., Hennig, Thomas, Rozina, Anna, Zhong, Yuhan, Lv, Shuangjuan, Bergant, Valter, Wang, Shuqi, Drge, Peter, Miller, Sven, Poptsova, Maria, Rehwinkel, Jan, Pichlmair, Andreas, Mocarski, Edward S., Thomas, Paul G., Dlken, Lars, Zhang, Ting, Herbert, Alan, Balachandran, Siddharth

Issue&Volume: 2025-10-13

Abstract: 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.

DOI: 10.1038/s41586-025-09705-5

Source: https://www.nature.com/articles/s41586-025-09705-5