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Review
. 2018 Feb;39(2):123-134.
doi: 10.1016/j.it.2017.11.002. Epub 2017 Nov 25.

ZBP1: Innate Sensor Regulating Cell Death and Inflammation

Teneema Kuriakose  1 , Thirumala-Devi Kanneganti  2
Affiliations
Review

ZBP1: Innate Sensor Regulating Cell Death and Inflammation

Teneema Kuriakose et al. Trends Immunol. 2018 Feb.

Abstract

Z-DNA-binding protein 1 (ZBP1), initially reported as an interferon (IFN)-inducible tumor-associated protein, harbors nucleic acid-binding domains for left-handed helix (Z-form) and receptor-interacting protein homotypic interaction motif (RHIM) domains for protein homotypic interactions. Recent studies have identified ZBP1 as an innate sensor of viral infections and a target of viral evasion strategies, regulating cell death, inflammasome activation, and proinflammatory responses. ZBP1 also functions during development and can trigger perinatal lethality when its RHIM-dependent interactions are not restricted VSports手机版. Here we review the history and emergence of ZBP1 as a pathogen sensor and a central regulator of cell death and inflammatory responses. We also discuss the gaps in our knowledge regarding the regulation and functions of ZBP1 and highlight potential avenues for future research. .

Keywords: DAI; RIPK1; RIPK3; ZBP1; caspase-8; cell death; inflammasome; inflammation; innate immunity V体育安卓版. .

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Figures

Figure 1
Figure 1. Domain structure of ZBP1
ZBP1 encodes two N-terminal Z-DNA binding domains, which is reported to bind with Z-DNA, B-DNA and RNA. ZBP1 also has two RHIM domains at the center part that facilitate interactions with other RHIM domain-containing proteins. These RHIM domains are important in mediating ZBP1—dependent cell death and inflammatory responses. The conserved C-terminal domains of ZBP1 were reported to interact with TBK1 and IRF3 to induce type I IFN responses to immunostimulatory DNA.
Figure 2
Figure 2. ZBP1 regulation of cell death and inflammatory responses during influenza virus infection
ZBP1 after sensing IAV infection associates with RIPK1 and RIPK3 kinases via RHIM domain interactions. ZBP1-RIPK3 complex activates parallel pathways of caspase-8-dependent apoptosis and MLKL-mediated necroptosis. In addition, ZBP1 regulates the NLRP3 inflammasome activation, pyroptosis and secretion of IL-1β and IL-18 via the RIPK3-caspase-8 axis. ZBP1-RIPK1 axis transduces downstream signaling and mediates secretion of various proinflammatory cytokines during IAV infection. ZBP1 regulation of cell death and inflammatory responses is also evident during in vivo infections and ZBP1 controls lung epithelial damage and inflammation during IAV infection.
Figure 3
Figure 3. ZBP1-RIPK1 axis in embryonic development and homeostasis
Aberrant activation of ZBP1 during embryonic development leads to necroptosis and perinatal lethality. When ZBP1 activity is not under check, it interacts with RIPK3 and activates MLKL-mediated necroptosis. The RHIM domain of RIPK1 inhibits activation of ZBP1 and its interaction with RIPK3 during development via yet unidentified mechanisms. The endogenous stimulus activating ZBP1 during development is not known.
Figure 4
Figure 4. ZBP1 sensing and regulation of necroptosis during MCMV infection
In addition to IAV, ZBP1 also functions as a sensor of MCMV infection and it interacts with newly transcribed viral gene products. Sensing and activation of ZBP1 leads to its interaction with RIPK3 and subsequent induction of necroptosis. The RHIM domain-containing virus protein M45 inhibits the ZBP1-RIPK3 complex formation and cell death during MCMV infection.
Figure 5
Figure 5. Schematic showing cancer-associated mutations in human ZBP1
Cancer-associated mutations in ZBP1 as per the Catalogue of Somatic Mutations in Cancer (COSMIC) database and Pediatric Cancer genome project depicted using ProteinPaint, (a web application for visualizing genomic data). The interactive tool is available at https://pecan.stjude.org/proteinpaint/ZBP1. Each color-coded circle depicts a mutation and the larger circles with numbers represent mutations found in more than one sample. This interactive tool allows visualization of major attributes of the mutation including the details of the sample from which the mutation was identified.
See this image and copyright information in PMC

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