ZBP1: A Powerful Innate Immune Sensor and Double-Edged Sword in Host Immunity

Abstract

Z-conformation nucleic acid binding protein 1 (ZBP1), a powerful innate immune sensor, has been identified as the important signaling initiation factor in innate immune response and the multiple inflammatory cell death known as PANoptosis. The initiation of ZBP1 signaling requires recognition of left-handed double-helix Z-nucleic acid (includes Z-DNA and Z-RNA) and subsequent signaling transduction depends on the interaction between ZBP1 and its adapter proteins, such as TANK-binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), receptor-interacting serine/threonine-protein kinase 1 (RIPK1), and RIPK3. ZBP1 activated innate immunity, including type-I interferon (IFN-I) response and NF-κB signaling, constitutes an important line of defense against pathogenic infection. In addition, ZBP1-mediated PANoptosis is a double-edged sword in anti-infection, auto-inflammatory diseases, and tumor immunity. ZBP1-mediated PANoptosis is beneficial for eliminating infected cells and tumor cells, but abnormal or excessive PANoptosis can lead to a strong inflammatory response that is harmful to the host. Thus, pathogens and host have each developed multiplex tactics targeting ZBP1 signaling to maintain strong virulence or immune homeostasis. In this paper, we reviewed the mechanisms of ZBP1 signaling, the effects of ZBP1 signaling on host immunity and pathogen infection, and various antagonistic strategies of host and pathogen against ZBP1. We also discuss existent gaps regarding ZBP1 signaling and forecast potential directions for future research.

ZBP1-mediated macrophage necroptosis inhibits ASFV replication

“…ZBP1 was originally identified as an innate immune sensor that activates interferon (IFN) responses and NF-κB signaling (43). Recently, ZBP1 has been reported as the master protein inducing PANoptosis (pyroptosis, apoptosis, and necroptosis) (29). Our past and present results confirmed that ZBP1 expression was upregulated in host macrophages upon ASFV infection (Fig.…”

“…The Zα domain of ZBP1 is important for sensing accumulated Z-NA and its nuclear migration (29,30). By reconstituting the Myc-tagged ZBP1 mutant plasmid lacking the Zα2 domain (Myc-ZBP1 ΔZα2 ) that based on the Myc-tagged porcine wild-type ZBP1 plasmid (Myc-ZBP1 WT ) (Fig.…”

Thiophene-Extended Fluorescent Nucleosides as Molecular Rotor-Type Fluorogenic Sensors for Biomolecular Interactions

“…Despite decades of research, structural information on, and the biological relevance of, Z-RNA are still lacking. Very recently, several seminal studies have revealed the intriguing function of Z-RNA as a pathogenic factor and demonstrated the importance of the Z-RNA-binding protein, which initiates an immune response in vivo. − These reports shed new light on Z-helix, Z-RNA/Z-DNA-binding domain-containing proteins, and their biological significance in gene regulation, innate immunity, and cancer diseases. Our group has been interested in Z-DNA/Z-RNA and has developed useful fluorescent nucleosides to detect the B–Z transition of DNA/RNA to investigate their interactions with proteins. ,− We have also developed a versatile nucleic acid-based FRET system that affords vivid fluorescence changes via a B–Z transition .…”

Identification of PANoptosis-relevant subgroups to evaluate the prognosis and immune landscape of patients with liver hepatocellular carcinoma

“…As a newly discovered programmed cell death mode, PANoptosis participates in fine-tuning anti-tumor immunity in TME by regulating the enrichment of immune cells and accelerating the death of tumor cells ( Hao et al, 2022 ; Liu et al, 2022 ). Only a few malignant tumors in advanced LIHC can be completely removed by surgery.…”