ZBP1/DAI drives RIPK3-Mediated cell death induced by IFNs in the absence of RIPK1

Justin P. Ingram, Roshan J. Thapa, Amanda Fisher, Bart Tummers, Ting Zhang, Chaoran Yin, Diego A. Rodriguez, Hongyan Guo, Rebecca Lane, Riley Williams, Michael J. Slifker, Suresh H. Basagoudanavar, Glenn F. Rall, Christopher P. Dillon, Douglas R. Green, William J. Kaiser, Siddharth Balachandran

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Receptor-interacting protein kinase 1 (RIPK1) regulates cell fate and proinflammatory signaling downstream of multiple innate immune pathways, including those initiated by TNF-α, TLR ligands, and IFNs. Genetic ablation of Ripk1 results in perinatal lethality arising from both RIPK3-mediated necroptosis and FADD/caspase-8-driven apoptosis. IFNs are thought to contribute to the lethality of Ripk1-deficient mice by activating inopportune cell death during parturition, but how IFNs activate cell death in the absence of RIPK1 is not understood. In this study, we show that Z-form nucleic acid binding protein 1 (ZBP1; also known as DAI) drives IFN-stimulated cell death in settings of RIPK1 deficiency. IFN-activated Jak/STAT signaling induces robust expression of ZBP1, which complexes with RIPK3 in the absence of RIPK1 to trigger RIPK3-driven pathways of caspase-8-mediated apoptosis and MLKL-driven necroptosis. In vivo, deletion of either Zbp1 or core IFN signaling components prolong viability of Ripk1-/- mice for up to 3 mo beyond parturition. Together, these studies implicate ZBP1 as the dominant activator of IFN-driven RIPK3 activation and perinatal lethality in the absence of RIPK1.

Original languageEnglish (US)
Pages (from-to)1348-1355
Number of pages8
JournalJournal of Immunology
Volume203
Issue number5
DOIs
StatePublished - Sep 1 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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