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.


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.

MeSH terms

  • Animals
  • Apoptosis*
  • Cell Line
  • Disease Models, Animal
  • Epithelial Cells / physiology
  • Epithelial Cells / virology
  • Fas-Associated Death Domain Protein / genetics
  • Fas-Associated Death Domain Protein / metabolism*
  • Fibroblasts / physiology
  • Fibroblasts / virology
  • Humans
  • Influenza A virus / growth & development*
  • Influenza A virus / immunology*
  • Mice
  • Mice, Knockout
  • Necrosis*
  • Orthomyxoviridae Infections / pathology
  • Protein Kinases / genetics
  • Protein Kinases / metabolism*
  • Protein Multimerization
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*


  • Fadd protein, mouse
  • Fas-Associated Death Domain Protein
  • MLKL protein, mouse
  • Protein Kinases
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • Ripk3 protein, mouse