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:32200799). 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 (By similarity). 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 (By similarity). 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). 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 (By similarity). 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 (By similarity). Also acts as the apical sensor of fungal infection responsible for activating PANoptosis (By similarity). Involved in CASP8-mediated cell death via its interaction with RIPK1 but independently of its ability to sense Z-RNAs (By similarity). In some cell types, also able to restrict viral replication by promoting cell death-independent responses (By similarity). In response to Zika virus 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 (By similarity). Itaconate inhibits the activity of succinate dehydrogenase, generating a metabolic state in neurons that suppresses replication of viral genomes (By similarity). (Microbial infection) In case of herpes simplex virus 1/HHV-1 infection, forms hetero-amyloid structures with HHV-1 protein RIR1/ICP6 which may inhibit ZBP1-mediated necroptosis, thereby preventing host cell death pathway and allowing viral evasion. 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 (By similarity). Interacts (via RIP homotypic interaction motif) with RIPK3; leading to RIPK3 activation and necroptosis; interaction is enhanced by CASP6 (By similarity). Interacts (via RIP homotypic interaction motif) with RIPK1 (By similarity). Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis) (By similarity). (Microbial infection) Interacts (via RIP homotypic interaction motif/RHIM) with herpes simplex virus 1/HHV-1 protein RIR1/ICP6 (via RHIM); this interaction may induce heteromeric amyloid assemblies and prevent necroptosis activation (PubMed:33348174). Interacts with human herpes simplex virus 1/HHV-1 protein ICP0 (Probable). Mainly cytoplasmic (PubMed:16876127, PubMed:16990255). Accumulates in the nucleus in response to influenza A virus (IAV) infection: senses IAV defective viral genomes RNA in the nucleus (By similarity). Compared to isoform 1, a higher proportion of this isoform is localized in the nucleus. Additional isoforms seem to exist. Highly expressed in lymphatic tissues including lymph node, leukocytes, tonsil, bone marrow and spleen (PubMed:11842111). Expressed to a lesser extent in thymus, lung and liver (PubMed:11842111). 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. The second Z-binding domain (also named Zalpha2) acts as a molecular switch regulating pyroptosis, necroptosis and apoptosis (PANoptosis). The second Z-binding domain is essential for sensing influenza A virus (IAV) Z-RNAs. (Microbial infection) The RIP homotypic interaction motif (RHIM) mediates interaction with the RHIM motif of the herpes simplex virus 1/HHV-1 protein RIR1/ICP6 to form hetero-amyloid structures. Phosphorylated. Spotting patterns - Issue 227 of August 2020