Human ZBP1 induces cell death-independent inflammatory signaling via RIPK3 and RIPK1

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ZBP1 is an interferon-induced cytosolic nucleic acid sensor that facilitates antiviral responses via RIPK3. Although ZBP1-mediated programmed cell death is widely described, whether and how it promotes inflammatory signaling is unclear. Here, we report a ZBP1-induced inflammatory signaling pathway mediated by K63- and M1-linked ubiquitin chains, which depends on RIPK1 and RIPK3 as scaffolds independently of cell death. In human HT29 cells, ZBP1 associated with RIPK1 and RIPK3 as well as ubiquitin ligases cIAP1 and LUBAC. ZBP1-induced K63- and M1-linked ubiquitination of RIPK1 and ZBP1 to promote TAK1- and IKK-mediated inflammatory signaling and cytokine production. Inhibition of caspase activity suppressed ZBP1-induced cell death but enhanced cytokine production in a RIPK1- and RIPK3 kinase activity-dependent manner. Lastly, we provide evidence that ZBP1 signaling contributes to SARS-CoV-2-induced cytokine production. Taken together, we describe a ZBP1-RIPK3-RIPK1-mediated inflammatory signaling pathway relayed by the scaffolding role of RIPKs and regulated by caspases, which may induce inflammation when ZBP1 is activated below the threshold needed to trigger a cell death response.

TidsskriftEMBO Reports
Udgave nummer23
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
This work was supported by the Ludwig Institute for Cancer Research Ltd. Work in the M.G‐H. lab was supported by a Wellcome Trust Fellowship (102894/Z/13/Z and 215612/Z/19/Z), the LEO foundation (from October 2020), and The Novo Nordisk Foundation (NNF20OC0059392, from December 2021). R.P. was supported by a China Scholarship Council‐University of Oxford DPhil Scholarship (2015‐2019; GAF1516_CSCUO_841725). S.R.P. was funded by The Independent Research Fund Denmark (0214‐00001B) the European Research Council (ERC‐AdG ENVISION; 786602), and the Novo Nordisk Foundation (NNF18OC0030274). We acknowledge the contribution to this study made by the Oxford Centre for Histopathology Research and the Oxford Radcliffe Biobank, which are supported by the University of Oxford, the Oxford CRUK Cancer Centre and the NIHR Oxford Biomedical Research Centre (Molecular Diagnostics Theme/Multimodal Pathology Subtheme), and the NIHR CRN Thames Valley network. We thank Prof. David Komander and Prof. Rune Busk Damgaard for providing Met1‐Ubiquitin antibody, Dr. Norbert Volkmar and Prof. John Christianson for providing shRNA plasmids targeting mismatch sequences, Tetralogic Pharmaceuticals for Compound A, Professor Georg Kochs, for providing SARS‐CoV‐2 virus stock, Dr. Amit Shrestha and Prof. Nick La Thangue for providing HL60 cells, and members of the M.G‐H. group for helpful suggestions and reading the manuscript.

Publisher Copyright:
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.

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