Host cell Z-RNAs activate ZBP1 during virus infections
Summary
This study shows that during infection by Herpes simplex virus 1 (HSV-1) and Influenza A virus (IAV) the innate sensor ZBP1 is activated mainly by host-derived Z-form RNAs (Z-RNAs), not viral RNAs. Those Z-RNAs arise from aberrant host transcripts produced when viruses disrupt transcription termination (a process called DoTT) by interfering with the Cleavage and Polyadenylation Specificity Factor (CPSF). Viral proteins ICP27 (HSV-1) and NS1 (IAV) drive DoTT; viruses lacking these factors fail to induce host Z-RNAs and stimulate ZBP1 poorly. Artificially expressing ICP27 or NS1, or pharmacologically blocking CPSF, is sufficient to generate host Z-RNAs and activate ZBP1. The work positions ZBP1-driven cell death as a host response to viral disruption of the transcriptional machinery.
Key Points
- ZBP1, a Z-RNA sensor that triggers programmed cell death, is activated during HSV-1 and IAV infections mainly by host-derived Z-RNAs rather than viral RNAs.
- The bulk of cellular Z-RNAs map to intergenic endogenous retroelements (EREs) within abnormally long 3′ extensions of host mRNAs.
- These aberrant transcripts result from Disruption of Transcription Termination (DoTT), caused by viral inhibition of CPSF-mediated 3′ processing.
- Viral proteins ICP27 (HSV-1) and NS1 (IAV) are responsible for blocking CPSF and triggering DoTT; mutant viruses lacking these proteins do not induce host Z-RNAs effectively and are attenuated in ZBP1 activation.
- Ectopic expression of ICP27 or NS1, or pharmacological CPSF blockade, is sufficient to drive accumulation of host Z-RNAs and activate ZBP1, demonstrating causality.
- The findings reframe ZBP1 activation as a host defence against virus-induced disruption of transcription rather than solely a response to viral nucleic acids.
Context and relevance
This paper revises our view of innate nucleic-acid sensing by showing that stressed or misprocessed host transcripts produced during infection can become the dominant ligands for a danger sensor. It links a well-described viral strategy (disruption of 3′ processing) to a discrete immune outcome (ZBP1-driven cell death), with implications for understanding viral pathogenesis and host tolerance. The result is relevant for researchers studying antiviral innate immunity, RNA biology, and the mechanisms viruses use to hijack host transcription. It may also influence approaches to modulate ZBP1 activity therapeutically in viral disease or inflammatory conditions where transcriptional termination is perturbed.
Why should I read this?
Short version: clever viruses mess up your mRNA finishing, and your own messed-up RNAs ring the alarm. If you care about how cells spot infection (or why some infections cause more damage), this paper explains a neat, unexpected route to immune activation and cell death — and it points to viral proteins you might target to stop that happening.