ZBP1 as a dynamic monitor of viral replication: implications for therapeutic strategies

Z-DNA binding protein 1 (ZBP1) is an innate immune sensor that recognizes Z-NAs, an atypical, left-handed nucleic acid structure produced during viral replication. This review contextualizes ZBP1 function within the spatiotemporal dynamics of the viral replication cycle, portraying it as a dynamic monitor rather than a static alarm. We discuss how the subcellular localization determines the signaling outcome (e.g., nuclear versus cytoplasmic sensing). Specifically, we discuss how ZBP1 functions as a dynamic molecular scaffold, where ligand-induced amyloid assembly concentrates downstream kinases to overcome cellular inhibition and initiate cell death. The review details ZBP1's dual antiviral strategy, encompassing NF-κB-mediated inflammation and PANoptotic cell death, and the resulting co-evolutionary dynamics, characterized by viral countermeasures such as 'signal masking' seen in poxvirus E3 and 'signal interception' utilized by herpesvirus ICP6. Finally, the dual immunomodulatory role of ZBP1 in driving immunopathology is analyzed. This replication-centric perspective provides a theoretical foundation for developing precise, stage-based therapies targeting the ZBP1 pathway.