Z-DNA-binding protein 1 (also known as DNA-dependent activator of IFN-regulatory factors (DAI) and DLM-1) is an intracellular protein in mammals that can activate an innate immune pathways to suppress the viral infection. ZENB1 senses left-handed (Z-form) double-helical Z-DNA and Z-RNA, which are pathogen-associated molecular patterns (PAMPs). It associates with Receptor Interacting Protein Kinase 3 (RIPK3) to initiate PANoptosis, a form of inflammatory programmed cell death.

During infection of human cells with influenza A virus (IAV) and HSV-1, host cell-derived Z-RNAs, arising from viral disruption of host transcription termination, are detected by ZBP1 to initiate NF-κB signalling and PANoptosis.

ZBP1 is an abbreviation for chicken or rat β-actin zipcode-binding protein 1. In humans, it is encoded by the ZBP1 gene. It is a homolog of the human insulin-like growth factor 2 mRNA-binding protein 1 (IMP-1) and murine CRD-BP, the proteins involved in mRNA transport (RNA-binding proteins, RBPs).

ZBP1 was first identified as an interferon-inducible Z-NA binding protein, but its specific functions remained unclear for many years. It was initially thought to be a cytosolic DNA sensor. However, the generation of Zbp1-deficient mice revealed that these mice responded normally to DNA and DNA virus infections, producing normal levels of interferon.

Further insights came with the discovery of ZBP1's receptor-interacting protein homotypic interaction motif (RHIM) domains, which mediate interactions with other proteins. Experiments showed that ZBP1 interacts with RIPK1 and RIPK3 through these RHIM domains. This interaction hinted at ZBP1's involvement in cell death, especially given the role of RIPK proteins in cell death pathways.

The role of ZBP1 as an innate immune sensor became more evident with the discovery that it regulates NLRP3 inflammasome activation and inflammatory cell death, PANoptosis, during influenza A virus infection. ZBP1-deficient mice showed impaired activation of inflammasome components, such as caspase-1, and reduced levels of IL-1β and IL-18, highlighting its critical role in antiviral defense.

ZBP1 has several key domains that contribute to its function. At the N-terminus, it has Z-nucleic acid (Z-NA) binding domains, known as Zα1 and Zα2. Both Zα domains have a winged helix-turn-helix structure which allows them to bind to Z-RNA/DNA. The intermediate region of ZBP1 contains two receptor-interacting protein homotypic interaction motif (RHIM) domains, RHIM1 and RHIM2, which facilitate interactions with other RHIM domain-containing proteins. The C-terminal region of ZBP1 contains a signal domain (SD), which is crucial for triggering an interferon response.

ZBP1 was discovered as an innate immune sensor of influenza A virus that forms the ZBP1-PANoptosome to activate the NLRP3 inflammasome and drive cell death, PANoptosis. PANoptosis is a prominent innate immune, inflammatory, and lytic cell death pathway initiated by innate immune sensors and driven by caspases and receptor-interacting protein kinases (RIPKs) through PANoptosomes. PANoptosomes are multi-protein complexes assembled by germline-encoded pattern-recognition receptor(s) (PRRs) (innate immune sensor(s)) in response to pathogens, including bacterial, viral, and fungal infections, as well as pathogen-associated molecular patterns, damage-associated molecular patterns, cytokines, and homeostatic changes during infections, inflammatory conditions, and cancer. Following the discoveries with IAV, the ZBP1-PANoptosome was also found to play a role in pathogenic inflammation in response to IFN therapy during coronavirus infection.