Viral Z-RNA triggers ZBP1-dependent cell death

• Type of Material: Article
• Authors: Siddharth Balachandran, Fox Chase Cancer Center; Edward Mocarski, Emory University
• Language: English
• Date: 2021-10-21
• Publisher: ELSEVIER SCI LTD
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 Elsevier B.V. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.coviro.2021.10.004
• Title of Journal or Parent Work: CURRENT OPINION IN VIROLOGY
• Volume: 51
• Start Page: 134
• End Page: 140
• Grant/Funding Information: Research relevant to this article was supported by NIH grants AI135025 and AI144400 (to SB) and AI020211 (to ESM).; SB is also supported by Cancer Center Support Grant P30CA006927.
• Keywords: Life Sciences & Biomedicine; PROGRAMMED NECROSIS; DEAMINASE ADAR1; Virology; FACTOR-ALPHA; PROTEIN; TUMOR-NECROSIS-FACTOR; Science & Technology; Z-DNA BINDING; DOUBLE-STRANDED-RNA; DOMAIN-LIKE; RIG-I; MIXED LINEAGE KINASE

Abstract

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 Zα 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’. VACV-generated Z-RNA accumulates in the cytoplasm, where it is sequestered from ZBP1 by E3, the viral E3L gene product. In viruses where the E3 Zα 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).