Influenza A virus (IAV) is a lytic RNA virus that triggers receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated pathways of apoptosis and mixed lineage kinase domain-like pseudokinase (MLKL)-dependent necroptosis in infected cells. ZBP1 initiates RIPK3-driven cell death by sensing IAV RNA and activating RIPK3. Here, we show that replicating IAV generates Z-RNAs, which activate ZBP1 in the nucleus of infected cells. ZBP1 then initiates RIPK3-mediated MLKL activation in the nucleus, resulting in nuclear envelope disruption, leakage of DNA into the cytosol, and eventual necroptosis. Cell death induced by nuclear MLKL was a potent activator of neutrophils, a cell type known to drive inflammatory pathology in virulent IAV disease. Consequently, MLKL-deficient mice manifest reduced nuclear disruption of lung epithelia, decreased neutrophil recruitment into infected lungs, and increased survival following a lethal dose of IAV. These results implicate Z-RNA as a new pathogen-associated molecular pattern and describe a ZBP1-initiated nucleus-to-plasma membrane "inside-out" death pathway with potentially pathogenic consequences in severe cases of influenza.
Keywords: MLKL; RIPK3; Z-RNA; ZBP1; apoptosis; caspase-8; dsRNA; influenza; necroptosis.
Copyright © 2020 Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of Interests The authors declare no competing interests.
RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation.Nature. 2016 Dec 1;540(7631):124-128. doi: 10.1038/nature20558. Epub 2016 Nov 7. Nature. 2016. PMID: 27819681 Free PMC article.
DAI Senses Influenza A Virus Genomic RNA and Activates RIPK3-Dependent Cell Death.Cell Host Microbe. 2016 Nov 9;20(5):674-681. doi: 10.1016/j.chom.2016.09.014. Epub 2016 Oct 13. Cell Host Microbe. 2016. PMID: 27746097 Free PMC article.
RIPK3 Activates Parallel Pathways of MLKL-Driven Necroptosis and FADD-Mediated Apoptosis to Protect against Influenza A Virus.Cell Host Microbe. 2016 Jul 13;20(1):13-24. doi: 10.1016/j.chom.2016.05.011. Epub 2016 Jun 16. Cell Host Microbe. 2016. PMID: 27321907 Free PMC article.
Benefits and Perils of Necroptosis in Influenza Virus Infection.J Virol. 2020 Apr 16;94(9):e01101-19. doi: 10.1128/JVI.01101-19. Print 2020 Apr 16. J Virol. 2020. PMID: 32051270 Review.
The Inflammatory Signal Adaptor RIPK3: Functions Beyond Necroptosis.Int Rev Cell Mol Biol. 2017;328:253-275. doi: 10.1016/bs.ircmb.2016.08.007. Epub 2016 Sep 22. Int Rev Cell Mol Biol. 2017. PMID: 28069136 Free PMC article. Review.
Cited by 1 article
Die Another Way: Interplay between Influenza A Virus, Inflammation and Cell Death.Viruses. 2020 Apr 4;12(4):401. doi: 10.3390/v12040401. Viruses. 2020. PMID: 32260457 Free PMC article. Review.
- R21 AI135709/AI/NIAID NIH HHS/United States
- R01 CA168621/CA/NCI NIH HHS/United States
- HHSN272201400006C/AI/NIAID NIH HHS/United States
- R01 AI144400/AI/NIAID NIH HHS/United States
- R01 AI121832/AI/NIAID NIH HHS/United States
- R37 AI044828/AI/NIAID NIH HHS/United States
- R01 CA190542/CA/NCI NIH HHS/United States
- R01 AI135025/AI/NIAID NIH HHS/United States
- R01 AI137062/AI/NIAID NIH HHS/United States
- R35 CA231620/CA/NCI NIH HHS/United States
- R01 AI044828/AI/NIAID NIH HHS/United States
- R01 AI134862/AI/NIAID NIH HHS/United States