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Host cell Z-RNAs activate ZBP1 during virus infections

Chaoran Yin1, Aleksandr Fedorov2,3, Hongyan Guo4

  • 1Center for Immunology, Fox Chase Cancer Center, Philadelphia, PA, USA.

Nature
|October 13, 2025
PubMed

Insights

Host cell Z-RNAs, not viral, activate Z-form-nucleic-acid-binding protein 1 (ZBP1) during herpes simplex virus 1 and influenza A virus infections. This cell death response counters viral disruption of host transcription.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Herpes simplex virus 1 (HSV-1) and influenza A viruses (IAV) trigger Z-form-nucleic-acid-binding protein 1 (ZBP1)-mediated cell death.
  • ZBP1 activation is typically induced by Z-RNA, previously assumed to be of viral origin during these infections.

Purpose of the Study:

  • To investigate the origin of Z-RNAs that activate ZBP1 during HSV-1 and IAV infections.
  • To elucidate the mechanism by which viruses trigger ZBP1-mediated cell death.

Main Methods:

  • Analysis of Z-RNA origins in HSV-1 and IAV infected cells.
  • Identification of host cell transcripts containing Z-RNAs.
  • Investigation of viral proteins (ICP27, NS1) and host factors (CPSF) in ZBP1 activation.
  • Assessment of viral attenuation in the absence of ZBP1 activation.

Main Results:

  • Host cell-encoded Z-RNAs, primarily from endogenous retroelements in extended mRNA 3' ends, are the major ZBP1-activating ligands.
  • Viral disruption of transcription termination (DoTT) leads to the accumulation of these host Z-RNAs.
  • Viruses lacking ICP27 or NS1, which inhibit CPSF and cause DoTT, fail to induce host Z-RNA accrual and are attenuated.
  • Ectopic expression of viral proteins or CPSF inhibition induces host Z-RNAs and activates ZBP1.

Conclusions:

  • DoTT-generated cellular Z-RNAs are sufficient ZBP1-activating ligands.
  • ZBP1-activated cell death serves as a host defense mechanism against viral interference with cellular transcription.

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