A FADD-dependent innate immune mechanism in mammalian cells.
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.
Balachandran
Siddharth
S
Department of Microbiology and Immunology and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida 33136, USA.
Thomas
Emmanuel
E
Barber
Glen N
GN
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D053200:Fas-Associated Death Domain Protein; D005347:Fibroblasts; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007370:Interferon Type I / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D018353:Rhabdoviridae Infections / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015398:Signal Transduction; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology / Q000502:physiology; D014779:Virus Replication
C119724:AGFG1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C505533:FADD protein, human; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D007370:Interferon Type I; D028861:Nuclear Pore Complex Proteins; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C506249:RIPK1 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C403191:TBK1 protein, human