ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways

By T. Kuriakose, S. Man, R. Malireddi, Rajendra Karki, S. Kesavardhana, David E. Place, G. Neale, P. Vogel, T. Kanneganti. Science immunology, 2016

736 citations recorded by the source corpus.

ZBP1 activates the NLRP3 inflammasome and programmed cell death. Sensing flu People infected with influenza get sick not only because of the presence of virus but also because of the inflammatory immune response. Now, Kuriakose et al. report that the protein ZBP1/DAI (Z-DNA binding protein 1/DNA-dependent activator of IFN regulatory factors) senses influenza A virus (IAV) and may contribute to this inflammatory pathogenesis. They found that ZBP1/DAI triggered cell death and inflammatory responses after IAV infection, and that ZBP1/DAI deficiency protected mice from IAV-related mortality. These mice had decreased inflammation and less epithelial damage than control animals. If these findings hold true in humans, ZBP1/DAI may be a host-directed target to decrease the severity of IAV pathogenesis. The interferon (IFN)–inducible protein Z-DNA binding protein 1 [ZBP1; also known as DNA-dependent activator of IFN regulatory factors (DAI) and DLM-1] was identified as a double-stranded DNA sensor, which instigates innate immune responses. However, this classification has been disputed, and whether ZBP1 functions as a pathogen sensor during an infection has remained unknown. We demonstrated ZBP1-mediated sensing of the influenza A virus (IAV) proteins NP and PB1, triggering cell death and inflammatory responses via the receptor-interacting protein kinase 1 (RIPK1)–RIPK3–caspase-8 axis. ZBP1 regulates NLRP3 (nucleotide and oligomerization domain, leucine-rich repeat–containing protein family, pyrin domain containing 3) inflammasome activation as well as induction of apoptosis, necroptosis, and pyroptosis in IAV-infected cells. ZBP1 deficiency protected mice from mortality during IAV infection owing to reduced inflammatory responses and epithelial damage. Overall, these findings indicate that ZBP1 is an innate immune sensor of IAV and highlight its importance in the pathogenesis of IAV infection.

Subfields: Epidemiology, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9c47240a77f906cebe2f8f9c93fb4ec713e3118e

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Citations in the corpus

Necroptosis, pyroptosis and apoptosis: an intricate game of cell death (2021, neutral): “It is somewhat more likely that these pathways are engaged in a cell type- and stimulusspecific manner, an explanation that would correspond better to the requirement for different upstream effectors and different subcellular localizations of NLRP3.”
Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 (2018, background): “IL18 signaling [620, 643, 644]; (2) TLR7, cyclic GMPAMP synthase (CGAS), transmembrane protein 173 (TMEM173; best known as STING), DExD/H-box helicase 58 (DDX58; best known as RIG-I), or mitochondrial antiviral signaling protein (MAVS) signaling upon bacterial or viral infection [525, 645]; or (3) t”
From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways (2021, positive): “Deletion of ZBP1 is sufﬁcient to suppress PANoptosis fully, whereas loss of individual components of the typical PCD pathways fails to rescue the cell death [22,27].”
NLRP3 inflammasome activation and cell death (2021, positive): “found that ZBP1 was a sensor of influenza virus (IAV) nucleoprotein and polymerase subunit PB1 and triggered NLRP3 inflammasome activation and proinflammatory cytokine production via the RIPK1–RIPK3–Caspase-8 axis [28].”
An update on the regulatory mechanisms of NLRP3 inflammasome activation (2021, background): “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 facilitat”
Synergism of TNF-α and IFN-γ Triggers Inflammatory Cell Death, Tissue Damage, and Mortality in SARS-CoV-2 Infection and Cytokine Shock Syndromes (2020, neutral): “…plays a critical role in regulating inflammatory cell death pathways, including pyroptosis and necroptosis (Fritsch et al., 2019; Gurung et al., 2014; 2016; Kuriakose et al., 2016; Lukens et al., 2014; Malireddi et al., 2020; 2018; Newton et al., 2019; Orning et al., 2018; Sarhan et al., 2018).”