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ZBP1 mediates interferon-induced necroptosis

Cellular & Molecular Immunology volume 17, pages 356–368 (2020)Cite this article

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Abstract

Interferons (IFNs) play an important role in immunomodulatory and antiviral functions. IFN-induced necroptosis has been reported in cells deficient in receptor-interacting protein kinase 1 (RIPK1), Fas-associated protein with death domain (FADD), or caspase-8, but the mechanism is largely unknown. Here, we report that the DNA-dependent activator of IFN regulatory factors (ZBP1, also known as DAI) is required for both type I (β) and type II (γ) IFN-induced necroptosis. We show that L929 fibroblast cells became susceptible to IFN-induced necroptosis when RIPK1, FADD, or Caspase-8 was genetically deleted, confirming the antinecroptotic role of these proteins in IFN signaling. We found that the pronecroptotic signal from IFN stimulation depends on new protein synthesis and identified ZBP1, an IFN-stimulated gene (ISG) product, as the de novo synthesized protein that triggers necroptosis in IFN-stimulated cells. The N-terminal domain (ND) of ZBP1 is important for ZBP1–ZBP1 homointeraction, and its RHIM domain in the C-terminal region interacts with RIPK3 to initiate RIPK3-dependent necroptosis. The antinecroptotic function of RIPK1, FADD, and caspase-8 in IFN-treated cells is most likely executed by caspase-8-mediated cleavage of RIPK3, since the inhibitory effect on necroptosis was eliminated when the caspase-8 cleavage site in RIPK3 was mutated. ZBP1-mediated necroptosis in IFN-treated cells is likely physiologically relevant, as ZBP1 KO mice were significantly protected against acute systemic inflammatory response syndrome (SIRS) induced by TNF + IFN-γ.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81788101), the National Basic Research Program of China (973 Program 2015CB553800), the National Natural Science Foundation of China (31420103910, 81630042, 31500737, and 31601122), the China Postdoctoral Science Foundation (2018T110638, 2017 M620267, and 2015T80680), the 111 Project (B12001), and the National Science Foundation of China for Fostering Talents in Basic Research (J1310027).

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  1. These authors contributed equally: Daowei Yang and Yaoji Liang

Authors and Affiliations

  1. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, 361005, Fujian, China

    Daowei Yang, Yaoji Liang, Shubo Zhao, Yan Ding, Qiuyu Zhuang, Qilin Shi, Tingting Ai, Su-Qin Wu & Jiahuai Han

  2. Department of Cancer Prevention Diagnosis and Treatment, Cancer Hospital, The First Affiliated Hospital of Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen, China

    Yaoji Liang

  3. School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102, Fujian, China

    Yaoji Liang

  4. XMU School of Pharmaceutical Sciences-Amogene Joint R&D Center for Genetic Diagnostics, Amogene Biotech, Xiamen, 361102, Fujian, China

    Yaoji Liang

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D. Y., Y. L., and J. H. conceived the study and wrote the manuscript; D. Y., S. Z., Y. D., and Q. Z. performed experiments; Q. S., T. A., and S. W. provided technical assistance.

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Correspondence to Jiahuai Han.

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Yang, D., Liang, Y., Zhao, S. et al. ZBP1 mediates interferon-induced necroptosis. Cell Mol Immunol 17, 356–368 (2020). https://doi.org/10.1038/s41423-019-0237-x

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