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

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  • Ruoshi Peng, University of Oxford
  • ,
  • Chris Kedong Wang, University of Copenhagen
  • ,
  • Xuan Wang-Kan, University of Oxford
  • ,
  • Manja Idorn
  • Majken Kjær, University of Copenhagen
  • ,
  • Felix Y. Zhou, University of Oxford
  • ,
  • Berthe Katrine Fiil, University of Copenhagen
  • ,
  • Frederik Timmermann, University of Copenhagen
  • ,
  • Susana L. Orozco, University of Washington
  • ,
  • Julia McCarthy, University of Oxford
  • ,
  • Carol S. Leung, University of Oxford
  • ,
  • Xin Lu, University of Oxford
  • ,
  • Katrin Bagola, University of Oxford, Paul-Ehrlich-Institut
  • ,
  • Jan Rehwinkel, University of Oxford
  • ,
  • Andrew Oberst, University of Washington
  • ,
  • Jonathan Maelfait, Ghent University
  • ,
  • Søren R. Paludan
  • Mads Gyrd-Hansen, University of Oxford, University of Copenhagen

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.

Original languageEnglish
Article numbere55839
JournalEMBO Reports
Number of pages23
Publication statusPublished - Dec 2022

    Research areas

  • inflammatory signaling, RIPK1, RIPK3, SARS-CoV-2, ZBP1

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