Key innate sensor that recognizes and binds Z-RNA structures, which are produced by a number of viruses, such as herpesvirus, orthomyxovirus or flavivirus, and triggers different forms of cell death (PubMed:17618271, PubMed:18375758, PubMed:19590578, PubMed:23283962, PubMed:27746097, PubMed:27917412, PubMed:27819681, PubMed:28716805, PubMed:28607035, PubMed:30050136, PubMed:31358656, PubMed:32200799, PubMed:32296175, PubMed:30498077, PubMed:29073079). ZBP1 acts as an essential mediator of pyroptosis, necroptosis and apoptosis (PANoptosis), an integral part of host defense against pathogens, by activating RIPK3, caspase-8 (CASP8), and the NLRP3 inflammasome (PubMed:27746097, PubMed:27917412, PubMed:28607035, PubMed:32200799, PubMed:32298652, PubMed:32350114, PubMed:32296175). Key activator of necroptosis, a programmed cell death process in response to death-inducing TNF-alpha family members, via its ability to bind Z-RNA: once activated upon Z-RNA-binding, ZBP1 interacts and stimulates RIPK3 kinase, which phosphorylates and activates MLKL, triggering execution of programmed necrosis (PubMed:22423968, PubMed:27746097, PubMed:27819681, PubMed:27819682, PubMed:28716805, PubMed:32200799, PubMed:32350114, PubMed:32315377, PubMed:32296175). In addition to TNF-induced necroptosis, necroptosis can also take place in the nucleus in response to orthomyxoviruses infection: ZBP1 recognizes and binds Z-RNA structures that are produced in infected nuclei by orthomyxoviruses, such as the influenza A virus (IAV), leading to ZBP1 activation, RIPK3 stimulation and subsequent MLKL phosphorylation, triggering disruption of the nuclear envelope and leakage of cellular DNA into the cytosol (PubMed:32200799, PubMed:32296175). ZBP1-dependent cell death in response to IAV infection promotes interleukin-1 alpha (IL1A) induction in an NLRP3-inflammasome-independent manner: IL1A expression is required for the optimal interleukin-1 beta (IL1B) production, and together, these cytokines promote infiltration of inflammatory neutrophils to the lung, leading to the formation of neutrophil extracellular traps (PubMed:31630209). In addition to its direct role in driving necroptosis via its ability to sense Z-RNAs, also involved in PANoptosis triggered in response to bacterial infection: component of the AIM2 PANoptosome complex, a multiprotein complex that triggers PANoptosis (PubMed:34471287). Also acts as the apical sensor of fungal infection responsible for activating PANoptosis (PubMed:33109609). Involved in CASP8-mediated cell death via its interaction with RIPK1 but independently of its ability to sense Z-RNAs (PubMed:33397971). In some cell types, also able to restrict viral replication by promoting cell death-independent responses (PubMed:30635240). In response to flavivirus infection in neurons, promotes a cell death-independent pathway that restricts viral replication: together with RIPK3, promotes a death-independent transcriptional program that modifies the cellular metabolism via up-regulation expression of the enzyme ACOD1/IRG1 and production of the metabolite itaconate (PubMed:30635240). Itaconate inhibits the activity of succinate dehydrogenase, generating a metabolic state in neurons that suppresses replication of viral genomes (PubMed:30635240). ZBP1-dependent necroptosis is normally inhibited by RIPK1: RIPK1 inhibits the ZBP1-induced activation of RIPK3 via FADD-mediated recruitment of CASP8, which cleaves RIPK1 and limits TNF-induced necroptosis. Homodimer (PubMed:18375758). Interacts (via RIP homotypic interaction motif) with RIPK3; leading to RIPK3 activation and necroptosis; interaction is enhanced by CASP6 (PubMed:19590578, PubMed:22423968, PubMed:27746097, PubMed:27819681, PubMed:27819682, PubMed:28607035, PubMed:32200799, PubMed:32298652). Interacts (via RIP homotypic interaction motif) with RIPK1 (PubMed:19590578, PubMed:23283962, PubMed:33397971). Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis) (PubMed:34471287). (Microbial infection) Interacts (via RIP homotypic interaction motif) with murid herpesvirus protein RIR1 (via RIP homotypic interaction motif); leading to inhibition of ZBP1-dependent necroptosis. (Microbial infection) Interacts with vaccinia virus E3 protein; leading to inhibit ZBP1-dependent necroptosis. Mainly cytoplasmic (PubMed:32200799). Accumulates in the nucleus in response to influenza A virus (IAV) infection: senses IAV defective viral genomes RNA in the nucleus (PubMed:32200799). Expressed in lung, spleen and liver. Lower levels were seen in heart, kidney and testis. Expression is greatly up-regulated in tumor stromal cells and activated macrophages. Expression is activated by IRF1 (PubMed:29321274). Up-regulated following interferon treatment (PubMed:10564822, PubMed:29073079). By lipopolysaccharides (LPS) (PubMed:10564822). The Z-binding domains recognize and bind left-handed double-stranded Z-RNA structures, but not A-RNA, the right-handed double-stranded RNAs that are structurally very different from Z-RNAs (PubMed:32200799). The second Z-binding domain (also named Zalpha2) acts as a molecular switch regulating pyroptosis, necroptosis and apoptosis (PANoptosis) (PubMed:32350114, PubMed:33109609). The second Z-binding domain is essential for sensing influenza A virus (IAV) Z-RNAs (PubMed:28607035, PubMed:28716805, PubMed:32350114). Ubiquitinated; polyubiquitinated following influenza A virus (IAV) infection. Phosphorylated. Mice are resistant to necroptosis, characterized by a decrease in epithelial cell death and an increase in virus replication (PubMed:22423968, PubMed:27746097, PubMed:27917412). At a modestly lethal dose of influenza A virus (IAV), mice display significantly increased rates of mortality, probably caused by a failure to eliminate infected cells and limit virus spread in pulmonary tissue (PubMed:32200799). Perinatal lethality observed in Ripk1 knockout mice is rescued in knockout mice lacking both Ripk1 and Zbp1 (PubMed:27819681, PubMed:27819682). Skin inflammation observed in Ripk1(mRHIM) mutant mice is abrogated in Ripk1(mRHIM) mutant mice that also lack Zbp1 (PubMed:27819681). According to a report, mice lacking Zbp1 display reductions in respiratory epithelial damage and lung inflammation (PubMed:27917412). However, the virus persists and replicates in the infected cells leading to a delay in recovery from infection, but the animals are protected from mortality (PubMed:27917412). In contrast, another article reported increased mortality in knockout mice, probably caused by increased virus burden (PubMed:27746097). However, as this study did not assess the inflammatory response in the lungs, it is difficult to compare ZBP1 regulation of lung inflammation between these two studies (PubMed:27746097).