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Human ZBP1 induces cell death-independent inflammatory signaling via RIPK3 and RIPK1.
Peng, Ruoshi; Wang, Chris Kedong; Wang-Kan, Xuan; Idorn, Manja; Kjaer, Majken; Zhou, Felix Y; Fiil, Berthe Katrine; Timmermann, Frederik; Orozco, Susana L; McCarthy, Julia; Leung, Carol S; Lu, Xin; Bagola, Katrin; Rehwinkel, Jan; Oberst, Andrew; Maelfait, Jonathan; Paludan, Søren R; Gyrd-Hansen, Mads.
Afiliación
  • Peng R; Nuffield Department of Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
  • Wang CK; Department of Immunology and Microbiology, LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark.
  • Wang-Kan X; Nuffield Department of Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
  • Idorn M; Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
  • Kjaer M; Department of Immunology and Microbiology, LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark.
  • Zhou FY; Nuffield Department of Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
  • Fiil BK; Department of Immunology and Microbiology, LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark.
  • Timmermann F; Department of Immunology and Microbiology, LEO Foundation Skin Immunology Research Center, University of Copenhagen, Copenhagen, Denmark.
  • Orozco SL; Department of Immunology, University of Washington, Seattle, WA, USA.
  • McCarthy J; Nuffield Department of Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
  • Leung CS; Nuffield Department of Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
  • Lu X; Nuffield Department of Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
  • Bagola K; Nuffield Department of Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
  • Rehwinkel J; Division of Immunology, Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich-Institut, Langen, Germany.
  • Oberst A; MRC Human Immunology Unit, Radcliffe Department of Medicine, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • Maelfait J; Department of Immunology, University of Washington, Seattle, WA, USA.
  • Paludan SR; VIB-UGent Center for Inflammation Research, Ghent, Belgium.
  • Gyrd-Hansen M; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
EMBO Rep ; 23(12): e55839, 2022 12 06.
Article en En | MEDLINE | ID: mdl-36268590
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Unión al ARN / Muerte Celular / Proteína Serina-Treonina Quinasas de Interacción con Receptores Límite: Humans Idioma: En Revista: EMBO Rep Asunto de la revista: BIOLOGIA MOLECULAR Año: 2022 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas de Unión al ARN / Muerte Celular / Proteína Serina-Treonina Quinasas de Interacción con Receptores Límite: Humans Idioma: En Revista: EMBO Rep Asunto de la revista: BIOLOGIA MOLECULAR Año: 2022 Tipo del documento: Article Pais de publicación: Reino Unido