ZBP1 Protein, Human (His)

ZBP1, a pivotal innate sensor, plays a crucial role in host defense against various viruses by recognizing and binding to Z-RNA structures produced by pathogens such as herpesvirus, orthomyxovirus, and flavivirus. This recognition triggers a spectrum of cell death responses, including pyroptosis, necroptosis, and apoptosis, collectively referred to as PANoptosis. ZBP1 serves as a key activator of necroptosis, particularly in response to death-inducing TNF-alpha family members, by binding Z-RNA and subsequently stimulating RIPK3 kinase, leading to the phosphorylation and activation of MLKL, ultimately executing programmed necrosis. Moreover, in the context of orthomyxovirus infection, ZBP1 detects Z-RNA structures in infected nuclei, activating RIPK3 and promoting MLKL phosphorylation, resulting in the disruption of the nuclear envelope and release of cellular DNA into the cytosol. ZBP1's role extends beyond direct pathogen sensing, as it is involved in PANoptosis triggered by bacterial and fungal infections. Notably, in response to Zika virus infection, ZBP1, in conjunction with RIPK3, initiates a death-independent transcriptional program that restricts viral replication by modifying cellular metabolism. However, in the case of herpes simplex virus 1 (HHV-1) infection, ZBP1 may form hetero-amyloid structures with HHV-1 protein RIR1/ICP6, potentially inhibiting ZBP1-mediated necroptosis and allowing viral evasion of host cell death pathways.