ZBP1 mediates interferon-induced necroptosis

Yang, Daowei; Liang, Yaoji; Zhao, Shubo; Ding, Yan; Zhuang, Qiuyu; Shi, Qilin; Ai, Tingting; Wu, Shuodong; Han, Jiahuai

doi:10.1038/s41423-019-0237-x

Cited by 123 publications

(107 citation statements)

References 54 publications

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“…Firstly, cultured primary RIPK1 keratinocytes, grown in sterile conditions, succumb to IFN-induced necroptosis, which crucially depended on the nucleic acid sensing capability of ZBP1. This is in agreement with earlier studies reporting on the toxicity of IFNs for RIPK1-deficient fibroblasts (Dillon et al, 2014;Kaiser et al, 2014), and which was recently shown to depend on ZBP1 (Ingram et al, 2019;Yang et al, 2019). Secondly, embryos expressing a mutant RIPK1 RHIM develop ZBP1-RIPK3-MLKL driven inflammatory epidermal hyperplasia at embryonic day 18.5, before exposure to microbes at birth (Lin et al, 2016;.…”

Section: Zbp1 Activation By Endogenous Nucleic Acids Induces Necroptosupporting

confidence: 92%

Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation

Devos

Tanghe

Gilbert

et al. 2020

Preprint

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Aberrant detection of endogenous nucleic acids by the immune system can cause inflammatory disease. The scaffold function of the signalling kinase RIPK1 limits spontaneous activation of the nucleic acid sensor ZBP1. Consequently, loss of RIPK1 in keratinocytes induces ZBP1-dependent necroptosis and skin inflammation. Whether nucleic acid sensing is required to activate ZBP1 in RIPK1 deficient conditions and which immune pathways are associated with skin disease remained open questions. Using knock-in mice with disrupted ZBP1 nucleic acid binding activity, we report that sensing of endogenous nucleic acids by ZBP1 is critical in driving skin pathology characterised by antiviral and IL-17 immune responses. Inducing ZBP1 expression by interferons triggers necroptosis in RIPK1-deficient keratinocytes and epidermis-specific deletion of MLKL prevents disease, demonstrating that cell-intrinsic events cause inflammation. These findings indicate that dysregulated sensing of endogenous nucleic acid by ZBP1 can drive inflammation and may contribute to the pathogenesis of IL-17-driven inflammatory skin conditions such as psoriasis.SummaryDevos, Tanghe et al. find that the recognition of endogenous nucleic acids by the nucleic acid sensor ZBP1 causes necroptosis of RIPK1-deficient keratinocytes. This process drives the development of an inflammatory skin disease characterised by an IL-17 immune response.

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Section: Zbp1 Activation By Endogenous Nucleic Acids Induces Necroptosupporting

confidence: 92%

Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation

Devos

Tanghe

Gilbert

et al. 2020

Preprint

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“…IAV infection in particular, has been shown to induce multiple forms of PCD, including both extrinsic and intrinsic apoptosis, necroptosis, and pyroptosis 22–26 . Strikingly, recent studies have identified several PRRs that can activate both antiviral and PCD pathways following viral infection 27,28 . Together these pathways, as well as pathways involved in host epithelium repair, play a pivotal role in dictating the severity and outcome of disease following IAV infection 7,29–32 .…”

Section: Introductionmentioning

confidence: 99%

Comprehensive single cell analysis of pandemic influenza A virus infection in the human airways uncovers cell-type specific host transcriptional signatures relevant for disease progression and pathogenesis

Kelly

Laloli

V’kovski

et al. 2020

Preprint

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Respiratory viruses, such as the 2009 pandemic strain of influenza A virus (IAV, H1N1pdm09), target cells found in the human respiratory epithelium. These cells, which form a pseudostratified epithelial layer along the airways, constitute the first line of defence against respiratory pathogens and play a crucial role in the host antiviral response. However, despite their key role in host defence, it remains unknown how distinct cell types in the respiratory epithelium respond to IAV infection and how these responses may contribute to IAV-induced pathogenesis and overall disease outcome. Here, we used single cell RNA-sequencing (scRNA-seq) to dissect the host response to IAV infection in its natural target cells. scRNA-seq was performed on human airway epithelial cell (hAEC) cultures infected with either wild-type pandemic IAV (WT) or with a mutant version of IAV (NS1R38A) that induced a robust innate immune response. We then characterized both the host and viral transcriptomes of more than 19,000 single cells across the 5 major cell types populating the human respiratory epithelium. For all cell types, we observed a wide spectrum of viral burden among single infected cells and a disparate host response between infected and bystander populations. Interestingly, we also identified multiple key differences in the host response to IAV among individual cell types, including high levels of pro-inflammatory cytokines and chemokines in secretory and basal cells and an important role for luminal cells in sensing and restricting incoming virus. Multiple infected cell types were shown to upregulate interferons (IFN), with type III IFNs clearly dominating the antiviral response. Transcriptional changes in genes related to cell differentiation, cell migration, and tissue repair were also identified. Strikingly, we also detected a shift in viral host cell tropism from non-ciliated cells to ciliated cells at later stages of infection and observed major changes in the cellular composition. Microscopic analysis of both WT and NS1R38A virus-infected hAECs at various stages of IAV infection revealed that the transcriptional changes we observed at 18 hpi were likely driving the downstream histopathological alterations in the airway epithelium. To our knowledge, this is the first study to provide a comprehensive analysis of the cell type-specific host antiviral response to a respiratory virus infection in its natural target cells – namely, the human respiratory epithelium.

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“…However, the host maintains cellular cross-talk between each programmed cell death pathway to subvert apoptosis inhibition and guard against pathogenic infection via necroptosis and pyroptosis (18). ZBP1 was found to mediate the interferon-induced necroptosis pathway in response to viral infection (27,28). ZBP1 as a PRR that induces immunity could fit within the realm of bacterial and parasitic infection (24,(54)(55)(56).…”

Section: Discussionmentioning

confidence: 99%

“…We also found ZBP1 to assist in host control of T. gondii infection in vitro and in vivo (24). Recently, IFN-γ has been shown to strongly induce ZBP1 to complex with RIPK3 to mediate inflammation and necroptosis as a host defense mechanism (25)(26)(27)(28). Here, we tested the hypothesis that ZBP1-dependent necroptosis is protective for T. gondii infection.…”

Section: Introductionmentioning

confidence: 88%

RIPK3 facilitates host and pathogen interactions after oralToxoplasma gondiiinfection

Cervantes

Knoll

2020

Preprint

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Toxoplasma gondii infection activates pattern recognition receptor (PRR) pathways that drive innate inflammatory responses to control infection. Necroptosis is a pro-inflammatory cell death pathway apart of the innate immune response that has evolved to control pathogenic infection. In this study we further defined the role of Z-DNA binding protein 1 (ZBP1) as a PRR and assessed its contribution to necroptosis as a host protection mechanism to T. gondii infection. We found that ZBP1 does not induce pro-inflammatory necroptosis cell death and ZBP1 null mice have reduced survival after oral T. gondii infection. In contrast, mice deleted in receptor-interacting serine/threonine-protein kinase 3 (RIPK3-/-), a central mediator of necroptosis, have significantly improved survival after oral T. gondii infection even with higher parasite burden. The physiological consequences of RIPK3 activity did not show any differences in intestine villi immunopathology but RIPK3-/- mice showed higher immune cell infiltration and edema in the lamina propria. The contribution of necroptosis to host survival was clarified with mixed lineage kinase domain like pseudokinase null (MLKL-/-) mice. We found MLKL-/- mice to succumb to oral T. gondii infection the same as wild type mice, indicating necroptosis-independent RIPK3 activity impacts host survival. These results provide new insights on the impacts of pro-inflammatory cell death pathways as a mechanism of host defense to oral T. gondii infection.

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ZBP1 mediates interferon-induced necroptosis

Cited by 123 publications

References 54 publications

Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation

Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation

Comprehensive single cell analysis of pandemic influenza A virus infection in the human airways uncovers cell-type specific host transcriptional signatures relevant for disease progression and pathogenesis

RIPK3 facilitates host and pathogen interactions after oralToxoplasma gondiiinfection

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