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Review
. 2022 Sep 6;23(18):10224.
doi: 10.3390/ijms231810224.

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

Yu Hao  1 , Bo Yang  1 , Jinke Yang  1 , Xijuan Shi  1 , Xing Yang  1 , Dajun Zhang  1 , Dengshuai Zhao  1 , Wenqian Yan  1 , Lingling Chen  1 , Haixue Zheng  1 , Keshan Zhang  1 , Xiangtao Liu  1
Affiliations
Review

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

Yu Hao et al. Int J Mol Sci. .

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.

Keywords: ZBP1; apoptosis; auto-inflammatory diseases; innate immunity; necroptosis; pathogen–host interactions; pyroptosis; signaling transduction; tumor immunity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Illustration of the domain structure of ZBP1. ZBP1 consists of two N-terminal Z-form nucleic acid binding domains, two RHIM domains of the intermediate segment, and the C-terminal domain.
Figure 2
Figure 2
The pattern of ZBP1-initiated PANoptosome assembly. The sensing of ZBP1 Zα for activated ligands allows ZBP1 interaction with RIPK1 and RIPK3 via RHIM domains and forms the core scaffolds of PANoptosome. RIPK3 induces the phosphorylation and membrane translocation of MLKL, which is the hallmark of necroptotic signaling. In addition, the homotypic interaction between RIPK1, FADD, and CASP8 liberates the cleaving activity of CASP8 and CASP3/7 that causes apoptosis. ZBP1-mediated apoptosis and necroptosis signaling promote the assembly and activation of NLRP3 inflammasome. Activated NLRP3 inflammasome matures GSDMD, IL-1β, and IL-18, named pyroptosis.
Figure 3
Figure 3
DNA viruses developed antagonistic mechanisms against ZBP1 signaling. After sensing virus-derived RNA, ZBP1 triggers necroptosis via the ZBP1-RIPK3-MLKL axis against MCMV, HSV-1, or VACV infection. However, the ZBP1 signaling is blocked by the DNA viruses-encoded virulence factors. At the beginning of the necroptosis signaling, the VACV E3 protein shields the VACV Z-RNA by its Zα domain and abolishes the activation of ZBP1. After that, the homologous RHIM of MCMV vIRA and HSV-1 ICP6 destroys the signaling transduction from ZBP1 to RIPK3.
Figure 4
Figure 4
The model for endogenous ZBP1 activation and the host antagonistic mechanisms targeting ZBP1 signaling. The endogenous retroviruses (ERV)-derived dsRNA, released cytoplasmic mitochondria DNA (mtDNA), and Z-RNA enriched in 3’UTR of ISGs mRNA that harbor inverted SINEs or GU-type simple repeats act as the activated ligands of ZBP1 and induce endogenous ZBP1 signaling. The endogenous activation of ZBP1 causes many auto-inflammatory diseases or stimulates tumor immunity. ADAR1-p150 inhibits the ligands sensing of ZBP1 by the Zα domain and RIPK1 blocks the signaling transduction of ZBP1 by its RHIM.
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Grants and funding

This work was supported by grants from the National Key R&D Program of China (2021YFD1801300); This work was supported by the major science and technology project of Gansu Province (20ZD7NA006-2, 21ZD3NA001); The Research funding from Lanzhou Veterinary Research Institue (CAAS-ZARW202006-03).