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

## TL;DR

ZBP1 acts as a dynamic immune sensor during viral replication, offering new insights for developing targeted antiviral therapies.

## Contribution

The paper presents ZBP1 as a dynamic monitor of viral replication, emphasizing its role in spatiotemporal signaling and therapeutic potential.

## Key findings

- ZBP1's subcellular localization determines its signaling outcome, such as nuclear or cytoplasmic sensing.
- ZBP1 uses amyloid assembly to concentrate kinases and initiate cell death, overcoming cellular inhibition.
- ZBP1's dual antiviral strategy includes inflammation and PANoptotic cell death, countered by viral mechanisms like signal masking and interception.

## Abstract

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.