DAI Senses Influenza A Virus Genomic RNA and Activates RIPK3-Dependent Cell Death

Overview

Journal Cell Host Microbe

Publisher Cell Press

Specialties Infectious Diseases
Microbiology

Date 2016 Oct 18

PMID 27746097

Citations 232

Authors

Roshan J Thapa

Justin P Ingram

Katherine B Ragan

Shoko Nogusa

David F Boyd

Asiel A Benitez

Haripriya Sridharan

Rachelle Kosoff

Maria Shubina

Vanessa J Landsteiner

Mark Andrake

Peter Vogel

Luis J Sigal

Benjamin R tenOever

Paul G Thomas

Jason W Upton

Siddharth Balachandran

Affiliations

Soon will be listed here.

Abstract

Influenza A virus (IAV) is an RNA virus that is cytotoxic to most cell types in which it replicates. IAV activates the host kinase RIPK3, which induces cell death via parallel pathways of necroptosis, driven by the pseudokinase MLKL, and apoptosis, dependent on the adaptor proteins RIPK1 and FADD. How IAV activates RIPK3 remains unknown. We report that DAI (ZBP1/DLM-1), previously implicated as a cytoplasmic DNA sensor, is essential for RIPK3 activation by IAV. Upon infection, DAI recognizes IAV genomic RNA, associates with RIPK3, and is required for recruitment of MLKL and RIPK1 to RIPK3. Cells lacking DAI or containing DAI mutants deficient in nucleic acid binding are resistant to IAV-triggered necroptosis and apoptosis. DAI-deficient mice fail to control IAV replication and succumb to lethal respiratory infection. These results identify DAI as a link between IAV replication and RIPK3 activation and implicate DAI as a sensor of RNA viruses.

Citing Articles

Innate Immune Sensors and Cell Death-Frontiers Coordinating Homeostasis, Immunity, and Inflammation in Skin.

Soe Y, Sim S, Kumari S Viruses. 2025; 17(2).

PMID: 40006996 PMC: 11861910. DOI: 10.3390/v17020241.

RIPK1 is required for ZBP1-driven necroptosis in human cells.

Amusan O, Wang S, Yin C, Koehler H, Li Y, Tenev T PLoS Biol. 2025; 23(2):e3002845.

PMID: 39982916 PMC: 11844899. DOI: 10.1371/journal.pbio.3002845.

Network pharmacology and experimental verification in vivo reveal the mechanism of Zhushao Granules against ulcerative colitis.

Gong B, Zhang C, Hu S, Zhang X, Zou H, Li J Biol Proced Online. 2025; 27(1):7.

PMID: 39953430 PMC: 11827476. DOI: 10.1186/s12575-025-00268-3.

ZBP1 senses DNA triggering type I interferon signaling pathway and unfolded protein response activation.

Gomes M, Guimaraes E, Oliveira S Front Immunol. 2025; 15:1511949.

PMID: 39850894 PMC: 11754416. DOI: 10.3389/fimmu.2024.1511949.

The Toxoplasma rhoptry protein ROP55 is a major virulence factor that prevents lytic host cell death.

Grilo Ruivo M, Shin J, Lenz T, Matsuno S, Yanes K, Graindorge A Nat Commun. 2025; 16(1):709.

PMID: 39814722 PMC: 11736080. DOI: 10.1038/s41467-025-56128-x.

References

Samuel C . Adenosine deaminases acting on RNA (ADARs) are both antiviral and proviral. Virology. 2011; 411(2):180-93. PMC: 3057271. DOI: 10.1016/j.virol.2010.12.004. View

Bergan V, Jagus R, Lauksund S, Kileng O, Robertsen B . The Atlantic salmon Z-DNA binding protein kinase phosphorylates translation initiation factor 2 alpha and constitutes a unique orthologue to the mammalian dsRNA-activated protein kinase R. FEBS J. 2007; 275(1):184-97. DOI: 10.1111/j.1742-4658.2007.06188.x. View

Cook W, Moujalled D, Ralph T, Lock P, Young S, Murphy J . RIPK1- and RIPK3-induced cell death mode is determined by target availability. Cell Death Differ. 2014; 21(10):1600-12. PMC: 4158685. DOI: 10.1038/cdd.2014.70. View

Zarling D, Calhoun C, Hardin C, Zarling A . Cytoplasmic Z-RNA. Proc Natl Acad Sci U S A. 1987; 84(17):6117-21. PMC: 299019. DOI: 10.1073/pnas.84.17.6117. View

Nogusa S, Thapa R, Dillon C, Liedmann S, Oguin 3rd T, Ingram J . RIPK3 Activates Parallel Pathways of MLKL-Driven Necroptosis and FADD-Mediated Apoptosis to Protect against Influenza A Virus. Cell Host Microbe. 2016; 20(1):13-24. PMC: 5026823. DOI: 10.1016/j.chom.2016.05.011. View

Kaiser W, Upton J, Mocarski E . Receptor-interacting protein homotypic interaction motif-dependent control of NF-kappa B activation via the DNA-dependent activator of IFN regulatory factors. J Immunol. 2008; 181(9):6427-34. PMC: 3104927. DOI: 10.4049/jimmunol.181.9.6427. View

Liu G, Park H, Pyo H, Liu Q, Zhou Y . Influenza A Virus Panhandle Structure Is Directly Involved in RIG-I Activation and Interferon Induction. J Virol. 2015; 89(11):6067-79. PMC: 4442436. DOI: 10.1128/JVI.00232-15. View

Orozco S, Yatim N, Werner M, Tran H, Gunja S, Tait S . RIPK1 both positively and negatively regulates RIPK3 oligomerization and necroptosis. Cell Death Differ. 2014; 21(10):1511-21. PMC: 4158689. DOI: 10.1038/cdd.2014.76. View

Ha S, Kim D, Hwang H, Rich A, Kim Y, Kim K . The crystal structure of the second Z-DNA binding domain of human DAI (ZBP1) in complex with Z-DNA reveals an unusual binding mode to Z-DNA. Proc Natl Acad Sci U S A. 2008; 105(52):20671-6. PMC: 2634953. DOI: 10.1073/pnas.0810463106. View

10.

Upton J, Kaiser W, Mocarski E . DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA. Cell Host Microbe. 2012; 11(3):290-7. PMC: 3531981. DOI: 10.1016/j.chom.2012.01.016. View

11.

Takaoka A, Wang Z, Choi M, Yanai H, Negishi H, Ban T . DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature. 2007; 448(7152):501-5. DOI: 10.1038/nature06013. View

12.

Herbert A, Alfken J, Kim Y, Mian I, Nishikura K, Rich A . A Z-DNA binding domain present in the human editing enzyme, double-stranded RNA adenosine deaminase. Proc Natl Acad Sci U S A. 1997; 94(16):8421-6. PMC: 22942. DOI: 10.1073/pnas.94.16.8421. View

13.

Manicassamy B, Manicassamy S, Belicha-Villanueva A, Pisanelli G, Pulendran B, Garcia-Sastre A . Analysis of in vivo dynamics of influenza virus infection in mice using a GFP reporter virus. Proc Natl Acad Sci U S A. 2010; 107(25):11531-6. PMC: 2895123. DOI: 10.1073/pnas.0914994107. View

14.

Nayak D, Chambers T, Akkina R . Defective-interfering (DI) RNAs of influenza viruses: origin, structure, expression, and interference. Curr Top Microbiol Immunol. 1985; 114:103-51. DOI: 10.1007/978-3-642-70227-3_3. View

15.

Ishii K, Kawagoe T, Koyama S, Matsui K, Kumar H, Kawai T . TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines. Nature. 2008; 451(7179):725-9. DOI: 10.1038/nature06537. View

16.

Kuriakose T, Man S, Malireddi R, Karki R, Kesavardhana S, Place D . ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways. Sci Immunol. 2016; 1(2). PMC: 5131924. DOI: 10.1126/sciimmunol.aag2045. View

17.

Tomescu A, Robb N, Hengrung N, Fodor E, Kapanidis A . Single-molecule FRET reveals a corkscrew RNA structure for the polymerase-bound influenza virus promoter. Proc Natl Acad Sci U S A. 2014; 111(32):E3335-42. PMC: 4136606. DOI: 10.1073/pnas.1406056111. View

18.

Athanasiadis A . Zalpha-domains: at the intersection between RNA editing and innate immunity. Semin Cell Dev Biol. 2011; 23(3):275-80. DOI: 10.1016/j.semcdb.2011.11.001. View

19.

Wittig B, Dorbic T, Rich A . Transcription is associated with Z-DNA formation in metabolically active permeabilized mammalian cell nuclei. Proc Natl Acad Sci U S A. 1991; 88(6):2259-63. PMC: 51210. DOI: 10.1073/pnas.88.6.2259. View

20.

Rosenberger C, Podyminogin R, Askovich P, Navarro G, Kaiser S, Sanders C . Characterization of innate responses to influenza virus infection in a novel lung type I epithelial cell model. J Gen Virol. 2013; 95(Pt 2):350-362. PMC: 3917066. DOI: 10.1099/vir.0.058438-0. View