DAI Senses Influenza A Virus Genomic RNA and Activates RIPK3-Dependent Cell Death

Influenza A virus (IAV) is an RNA virus that is cytotoxic to most cell types in which it replicates. IAV activates the host kinase RIPK3, which induces cell death via parallel pathways of necroptosis, driven by the pseudokinase MLKL, and apoptosis, dependent on the adaptor proteins RIPK1 and FADD. How IAV activates RIPK3 remains unknown. We report that DAI (ZBP1/DLM-1), previously implicated as a cytoplasmic DNA sensor, is essential for RIPK3 activation by IAV. Upon infection, DAI recognizes IAV genomic RNA, associates with RIPK3, and is required for recruitment of MLKL and RIPK1 to RIPK3. Cells lacking DAI or containing DAI mutants deficient in nucleic acid binding are resistant to IAV-triggered necroptosis and apoptosis. DAI-deficient mice fail to control IAV replication and succumb to lethal respiratory infection. These results identify DAI as a link between IAV replication and RIPK3 activation and implicate DAI as a sensor of RNA viruses. [Display omitted] •DAI is essential for influenza A virus (IAV)-triggered apoptosis and necroptosis•DAI senses IAV genomic RNA•DAI nucleates a RIPK3 necrosome containing adaptors RIPK1 and MLKL•DAI is required to control IAV replication in vivo Influenza A viruses (IAV) trigger RIPK3-dependent death in infected cells. Thapa et al. identify the host protein DAI as the link between replicating IAV and RIPK3 activation. DAI senses IAV genomic RNA, binds RIPK3, and triggers both apoptosis and necroptosis to eliminate the infected cell and protect the host.