RIPK3 Activates Parallel Pathways of MLKL-Driven Necroptosis and FADD-Mediated Apoptosis to Protect Against Influenza A Virus

Overview

Journal Cell Host Microbe

Publisher Cell Press

Specialties Infectious Diseases
Microbiology

Date 2016 Jun 21

PMID 27321907

Citations 219

Authors

Shoko Nogusa

Roshan J Thapa

Christopher P Dillon

Swantje Liedmann

Thomas H Oguin 3rd

Justin P Ingram

Diego A Rodriguez

Rachelle Kosoff

Shalini Sharma

Oliver Sturm

Katherine Verbist

Peter J Gough

John Bertin

Boris M Hartmann

Stuart C Sealfon

William J Kaiser

Edward S Mocarski

Carolina B Lopez

Paul G Thomas

Andrew Oberst

Douglas R Green

Siddharth Balachandran

Affiliations

Soon will be listed here.

Abstract

Influenza A virus (IAV) is a lytic virus in primary cultures of many cell types and in vivo. We report that the kinase RIPK3 is essential for IAV-induced lysis of mammalian fibroblasts and lung epithelial cells. Replicating IAV drives assembly of a RIPK3-containing complex that includes the kinase RIPK1, the pseudokinase MLKL, and the adaptor protein FADD, and forms independently of signaling by RNA-sensing innate immune receptors (RLRs, TLRs, PKR), or the cytokines type I interferons and TNF-α. Downstream of RIPK3, IAV activates parallel pathways of MLKL-driven necroptosis and FADD-mediated apoptosis, with the former reliant on RIPK3 kinase activity and neither on RIPK1 activity. Mice deficient in RIPK3 or doubly deficient in MLKL and FADD, but not MLKL alone, are more susceptible to IAV than their wild-type counterparts, revealing an important role for RIPK3-mediated apoptosis in antiviral immunity. Collectively, these results outline RIPK3-activated cytolytic mechanisms essential for controlling respiratory IAV infection.

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References

Lawlor K, Khan N, Mildenhall A, Gerlic M, Croker B, DCruz A . RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nat Commun. 2015; 6:6282. PMC: 4346630. DOI: 10.1038/ncomms7282. View

Newton K, Dugger D, Wickliffe K, Kapoor N, de Almagro M, Vucic D . Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science. 2014; 343(6177):1357-60. DOI: 10.1126/science.1249361. View

Sanders C, Doherty P, Thomas P . Respiratory epithelial cells in innate immunity to influenza virus infection. Cell Tissue Res. 2010; 343(1):13-21. DOI: 10.1007/s00441-010-1043-z. View

Cho Y, Challa S, Moquin D, Genga R, Ray T, Guildford M . Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 2009; 137(6):1112-23. PMC: 2727676. DOI: 10.1016/j.cell.2009.05.037. View

Berger S, Kasparcova V, Hoffman S, Swift B, Dare L, Schaeffer M . Cutting Edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. J Immunol. 2014; 192(12):5476-80. PMC: 4048763. DOI: 10.4049/jimmunol.1400499. 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

Ichinohe T, Lee H, Ogura Y, Flavell R, Iwasaki A . Inflammasome recognition of influenza virus is essential for adaptive immune responses. J Exp Med. 2009; 206(1):79-87. PMC: 2626661. DOI: 10.1084/jem.20081667. View

Mocarski E, Kaiser W, Livingston-Rosanoff D, Upton J, Daley-Bauer L . True grit: programmed necrosis in antiviral host defense, inflammation, and immunogenicity. J Immunol. 2014; 192(5):2019-26. PMC: 3934821. DOI: 10.4049/jimmunol.1302426. View

Harris P, Bandyopadhyay D, Berger S, Campobasso N, Capriotti C, Cox J . Discovery of Small Molecule RIP1 Kinase Inhibitors for the Treatment of Pathologies Associated with Necroptosis. ACS Med Chem Lett. 2014; 4(12):1238-43. PMC: 4027519. DOI: 10.1021/ml400382p. View

10.

Yeh W, de la Pompa J, McCurrach M, Shu H, Elia A, Shahinian A . FADD: essential for embryo development and signaling from some, but not all, inducers of apoptosis. Science. 1998; 279(5358):1954-8. DOI: 10.1126/science.279.5358.1954. View

11.

Pasparakis M, Vandenabeele P . Necroptosis and its role in inflammation. Nature. 2015; 517(7534):311-20. DOI: 10.1038/nature14191. View

12.

Yatim N, Albert M . Dying to replicate: the orchestration of the viral life cycle, cell death pathways, and immunity. Immunity. 2011; 35(4):478-90. DOI: 10.1016/j.immuni.2011.10.010. View

13.

Hoffmann E, Krauss S, Perez D, Webby R, Webster R . Eight-plasmid system for rapid generation of influenza virus vaccines. Vaccine. 2002; 20(25-26):3165-70. DOI: 10.1016/s0264-410x(02)00268-2. View

14.

Po J, Gardner E, Anaraki F, Katsikis P, Murasko D . Age-associated decrease in virus-specific CD8+ T lymphocytes during primary influenza infection. Mech Ageing Dev. 2002; 123(8):1167-81. DOI: 10.1016/s0047-6374(02)00010-6. View

15.

Polykratis A, Hermance N, Zelic M, Roderick J, Kim C, Van T . Cutting edge: RIPK1 Kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo. J Immunol. 2014; 193(4):1539-1543. PMC: 4119562. DOI: 10.4049/jimmunol.1400590. View

16.

Allen I, Scull M, Moore C, Holl E, McElvania-TeKippe E, Taxman D . The NLRP3 inflammasome mediates in vivo innate immunity to influenza A virus through recognition of viral RNA. Immunity. 2009; 30(4):556-65. PMC: 2803103. DOI: 10.1016/j.immuni.2009.02.005. View

17.

Vaux D, Haecker G, Strasser A . An evolutionary perspective on apoptosis. Cell. 1994; 76(5):777-9. DOI: 10.1016/0092-8674(94)90350-6. View

18.

Wang X, Jiang W, Yan Y, Gong T, Han J, Tian Z . RNA viruses promote activation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathway. Nat Immunol. 2014; 15(12):1126-33. DOI: 10.1038/ni.3015. View

19.

Kash J, Tumpey T, Proll S, Carter V, Perwitasari O, Thomas M . Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus. Nature. 2006; 443(7111):578-81. PMC: 2615558. DOI: 10.1038/nature05181. View

20.

Vandenabeele P, Declercq W, Van Herreweghe F, Vanden Berghe T . The role of the kinases RIP1 and RIP3 in TNF-induced necrosis. Sci Signal. 2010; 3(115):re4. DOI: 10.1126/scisignal.3115re4. View