Viral Z-RNA triggers ZBP1-dependent cell death

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• Z-DNA Binding protein 1 (ZBP1) is known to induce cell death.
• ZBP1 has Zα domains that bind Z-DNA and Z-RNA.
• RIPK3-dependent necroptosis is a key cell death pathway.

Purpose of the Study:

• To identify the ZBP1 ligand during viral infections.
• To elucidate the mechanism of ZBP1 activation by Z-RNA.
• To characterize Z-RNA as a viral pathogen-associated molecular pattern (PAMP).

Main Methods:

• Cell-based assays to detect ZBP1 activation.
• Viral infection models (orthomyxoviruses, vaccinia virus).
• Analysis of Z-RNA localization and ZBP1 interaction.

Main Results:

• Z-RNA, not Z-DNA, activates ZBP1 during infection with influenza and vaccinia viruses.
• Orthomyxovirus Z-RNA triggers nuclear ZBP1-RIPK3 signaling, leading to nuclear necroptosis.
• Vaccinia virus E3L protein sequesters Z-RNA in the cytoplasm, preventing ZBP1 activation unless E3L is mutated.

Conclusions:

• Z-RNA is the direct ZBP1 ligand during infection with specific viruses.
• ZBP1 activation by Z-RNA leads to distinct necroptotic outcomes based on viral strategy.
• Z-RNA represents a newly identified viral PAMP that triggers innate immune responses.