Viral Z-RNA triggers ZBP1-dependent cell death

Z-DNA Binding protein 1 (ZBP1) activates Receptor Interacting Protein Kinase 3 (RIPK3)-dependent cell death during lytic infection by members of the orthomyxovirus, herpesvirus and poxvirus families. ZBP1 possesses two Za domains capable of selective binding to Z-DNA, as well as to Z-RNA. We have now unveiled Z-RNA as the ligand that activates ZBP1 in cells infected with orthomyxoviruses (influenza A and B viruses) and the poxvirus vaccinia virus (VACV). Orthomyxovirus Z-RNA is sensed by ZBP1 in the nucleus of infected cells, resulting in nuclear activation of RIPK3, consequent rupture of the nucleus, and hyper-inflammatory 'nuclear necroptosis'. VACVgenerated Z-RNA accumulates in the cytoplasm, where it is sequestered from ZBP1 by E3, the viral E3L gene product. In viruses where the E3 Za domain has been mutated, ZBP1 senses Z-RNA and triggers RIPK3-dependent necroptosis in the cytoplasm. Z-RNA is thus a new viral pathogen-associated molecular pattern (PAMP).

Automated summary

ZBP1 is a Z-DNA binding protein that can be activated by Z-RNA in cells infected with orthomyxoviruses and poxviruses, leading to cell death. Z-RNA is sensed in the nucleus of infected cells, but can be sequestered by the viral gene product E3 in the cytoplasm.