Zα2 domain of ZBP1 is a molecular switch regulating Influenza-induced PANoptosis and perinatal lethality during development

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Z-DNA-binding protein 1 (ZBP1) is an innate nucleic acid sensor which regulates host defense responses and development. ZBP1 activation triggers inflammation and pyroptosis, necroptosis, and apoptosis (PANoptosis) by activating RIPK3, caspase-8, and the NLRP3 inflammasome. ZBP1 is unique among innate sensors because of its N-terminal Zα1 and Zα2 domains, which bind to nucleic acids in the Z-conformation. However, the specific role of these Zα domains in orchestrating ZBP1 activation and subsequent inflammation and cell death is not clear. Here we have generated <jats:italic>Zbp1</jats:italic><jats:sup>Δ<jats:italic>Z</jats:italic>α2/Δ<jats:italic>Z</jats:italic>α2</jats:sup> mice that lack the Zα2 domain of ZBP1 and demonstrate that this domain is critical for influenza A virus (IAV)-induced PANoptosis and perinatal lethality in RIPK1-RHIM mutated (<jats:italic>Ripk1</jats:italic><jats:sup>RHIM/RHIM</jats:sup>) mice. Deletion of the Zα2 domain in ZBP1 abolished IAV-induced PANoptosis and NLRP3 inflammasome activation. Furthermore, deletion of the Zα2 domain of ZBP1 was sufficient to rescue <jats:italic>Ripk1</jats:italic><jats:sup>RHIM/RHIM</jats:sup> mice from the perinatal lethality which is caused by ZBP1-driven cell death and inflammation. Our findings identify the essential role of the Zα2 domain of ZBP1 in physiological functions and establish a link between sensing of Z-RNAs via the Zα2 domain and the promotion of influenza-induced PANoptosis and perinatal lethality.</jats:p>

The Role of the Z-DNA Binding Domain in Innate Immunity and Stress Granules

“…The Z-RNA generated from anti-sense Influenza A virus (IAV) triggers RIPK3-MLKL-mediated necroptosis, where nuclear envelope collapse in infected cells leads to cell death and neutrophil recruitment ( 105 ). In another study, the second Zα ZBP1 is found to be essential for influenza-induced PAN-optosis ( 106 ). For Herpes simplex virus (a DNA virus), ZBP1-mediated necroptosis is thought to be activated through interaction with viral RNA transcripts, instead of viral DNA ( 107 ).…”

An update on the regulatory mechanisms of NLRP3 inflammasome activation

“…24,[166][167][168] The ZBP1 Zα2 domain is crucial for influenza A virus (IAV)-induced PANoptosis, NLRP3 inflammasome activation, and perinatal lethality, which are associated with hyperinflammation and epithelial damage. 166,169 In addition, caspase-6 is required for ZBP1-mediated inflammasome activation by facilitating the binding of RIPK3 to ZBP1. 170 Furthermore, IFN regulatory factor (IRF)1 is a transcriptional regulator of ZBP1 and promotes activation of the NLRP3 inflammasome and induces cell death during IAV infection.…”

Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes

“…PANoptosis is defined as a unique, physiologically relevant, inflammatory programmed cell death pathway activated by specific triggers and regulated by the PANoptosome complex. The PANoptosome provides a molecular scaffold for contemporaneous engagement of key molecules from pyroptosis, apoptosis, and necroptosis (Christgen et al, 2020;Karki et al, 2020;Kesavardhana et al, 2020;Malireddi et al, 2020;Samir et al, 2020;Zheng et al, 2020a;. Currently, there is a critical shortage of proven treatment options for the ongoing COVID-19 pandemic, leading to an urgent need to understand the pathogenesis of multi-organ failure and lung damage in these patients.…”