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Ingram JP , Thapa RJ , Fisher A , Tummers B , Zhang T , Yin C , Rodriguez DA , Guo H , Lane R , Williams R , Slifker MJ , Basagoudanavar SH , Rall GF , Dillon CP , Green DR , Kaiser WJ , Balachandran S
ZBP1/DAI Drives RIPK3-Mediated Cell Death Induced by IFNs in the Absence of RIPK1
J Immunol. 2019 Sep 1;203(5) :1348-1355
PMID: 31358656    PMCID: PMC6702065    URL: https://www.ncbi.nlm.nih.gov/pubmed/31358656
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Receptor-interacting protein kinase 1 (RIPK1) regulates cell fate and proinflammatory signaling downstream of multiple innate immune pathways, including those initiated by TNF-alpha, 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.
1550-6606 Ingram, Justin P Thapa, Roshan J ORCID: http://orcid.org/0000-0002-1852-0616 Fisher, Amanda ORCID: http://orcid.org/0000-0002-2634-144X Tummers, Bart Zhang, Ting Yin, Chaoran Rodriguez, Diego A ORCID: http://orcid.org/0000-0003-4771-0221 Guo, Hongyan Lane, Rebecca Williams, Riley Slifker, Michael J ORCID: http://orcid.org/0000-0002-9718-5966 Basagoudanavar, Suresh H ORCID: http://orcid.org/0000-0001-7714-3120 Rall, Glenn F Dillon, Christopher P Green, Douglas R Kaiser, William J Balachandran, Siddharth Journal Article United States P30 CA006927/CA/NCI NIH HHS/ J Immunol. 2019 Sep 1;203(5):1348-1355. doi: 10.4049/jimmunol.1900216. Epub 2019 Jul 29.