A FADD-dependent innate immune mechanism in mammalian cells

Nature. 2004 Nov 18;432(7015):401-5. doi: 10.1038/nature03124.

Abstract

Vertebrate innate immunity provides a first line of defence against pathogens such as viruses and bacteria. Viral infection activates a potent innate immune response, which can be triggered by double-stranded (ds)RNA produced during viral replication. Here, we report that mammalian cells lacking the death-domain-containing protein FADD are defective in intracellular dsRNA-activated gene expression, including production of type I (alpha/beta) interferons, and are thus very susceptible to viral infection. The signalling pathway incorporating FADD is largely independent of Toll-like receptor 3 and the dsRNA-dependent kinase PKR, but seems to require receptor interacting protein 1 as well as Tank-binding kinase 1-mediated activation of the transcription factor IRF-3. The requirement for FADD in mammalian host defence is evocative of innate immune signalling in Drosophila, in which a FADD-dependent pathway responds to bacterial infection by activating the transcription of antimicrobial genes. These data therefore suggest the existence of a conserved pathogen recognition pathway in mammalian cells that is essential for the optimal induction of type I interferons and other genes important for host defence.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Line
  • Fas-Associated Death Domain Protein
  • Fibroblasts
  • Gene Deletion
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • Immunity, Innate / immunology*
  • Interferon Type I / deficiency
  • Interferon Type I / genetics
  • Interferon Type I / immunology
  • Interferon Type I / metabolism
  • Mice
  • Nuclear Pore Complex Proteins / genetics
  • Nuclear Pore Complex Proteins / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Double-Stranded / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Rhabdoviridae Infections / immunology
  • Rhabdoviridae Infections / metabolism
  • Rhabdoviridae Infections / virology
  • Signal Transduction
  • Vesicular stomatitis Indiana virus / immunology
  • Vesicular stomatitis Indiana virus / physiology
  • Virus Replication

Substances

  • AGFG1 protein, human
  • Adaptor Proteins, Signal Transducing
  • FADD protein, human
  • Fadd protein, mouse
  • Fas-Associated Death Domain Protein
  • Interferon Type I
  • Nuclear Pore Complex Proteins
  • RNA, Double-Stranded
  • RNA, Messenger
  • RNA-Binding Proteins
  • Tbk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • TBK1 protein, human