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Cell Host Microbe. 2016 Jul 13;20(1):13-24. doi: 10.1016/j.chom.2016.05.011. Epub 2016 Jun 16.

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

Author information

1
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
2
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
3
Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA.
4
Department of Neurology, Icahn School of Medicine at Mt. Sinai, New York, NY 10029, USA.
5
Emory Vaccine Center, Emory University, Atlanta, GA 30322, USA.
6
School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
7
Department of Microbiology and Immunology, University of Washington, Seattle, WA 98109, USA.
8
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: douglas.green@stjude.org.
9
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. Electronic address: siddharth.balachandran@fccc.edu.

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.

PMID:
27321907
PMCID:
PMC5026823
DOI:
10.1016/j.chom.2016.05.011
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest. Peter J. Gough and John Bertin are employees of GlaxoSmithKline.

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