Sensing of viral and endogenous RNA by ZBP 1/ DAI induces necroptosis

Nucleic acids are potent triggers for innate immunity. Double‐stranded DNA and RNA adopt different helical conformations, including the unusual Z‐conformation. Z‐ DNA / RNA is recognised by Z‐binding domains ( ZBD s), which are present in proteins implicated in antiviral immunity. These include ZBP 1 (also known as DAI or DLM ‐1), which induces necroptosis, an inflammatory form of cell death. Using reconstitution and knock‐in models, we report that mutation of key amino acids involved in Z‐ DNA / RNA binding in ZBP 1's ZBD s prevented necroptosis upon infection with mouse cytomegalovirus. Induction of cell death was cell autonomous and required RNA synthesis but not viral DNA replication. Accordingly, ZBP 1 directly bound to RNA via its ZBD s. Intact ZBP 1‐ ZBD s were also required for necroptosis triggered by ectopic expression of ZBP 1 and caspase blockade, and ZBP 1 cross‐linked to endogenous RNA . These observations show that Z‐ RNA may constitute a molecular pattern that induces inflammatory cell death upon sensing by ZBP 1.