Mechanisms of the TRIF-induced interferon-stimulated response element and NF-kappaB activation and apoptosis pathways.
Toll-like receptor-3 is critically involved in host defense against viruses through induction of type I interferons (IFNs). Recent studies suggest that a Toll/interleukin-1 receptor domain-containing adapter protein (TRIF) and two protein kinases (TANK-binding kinase-1 (TBK1) and IkappaB kinase (IKK)-epsilon) are critically involved in Toll-like receptor-3-mediated IFN-beta production through activation of IFN regulatory factor (IRF)-3 and IRF-7. In this study, we demonstrate that TRIF interacts with both IRF-7 and IRF-3. In addition to TBK1 and IKKepsilon, our results indicate that IKKbeta can also phosphorylate IRF-3 and activate the IFN-stimulated response element. TRIF-induced IRF-3 and IRF-7 activation was mediated by TBK1 and its downstream kinases IKKbeta and IKKepsilon. TRIF induced NF-kappaB activation through an IKKbeta- and tumor necrosis factor receptor-associated factor-6-dependent (but not TBK1- and IKKepsilon-dependent) pathway. In addition, TRIF also induced apoptosis through a RIP/FADD/caspase-8-dependent and mitochondrion-independent pathway. Furthermore, our results suggest that the TRIF-induced IFN-stimulated response element and NF-kappaB activation and apoptosis pathways are uncoupled and provide a molecular explanation for the divergent effects induced by the adapter protein TRIF.
Han
Ke-Jun
KJ
Department of Immunology, National Jewish Medical and Research Center, University of Colorado Health Sciences Center, Denver, Colorado 80206, USA. shuh@njc.org
Su
Xiaoqin
X
Xu
Liang-Guo
LG
Bin
Liang-Hua
LH
Zhang
Jun
J
Shu
Hong-Bing
HB
D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D053938:DNA Fragmentation; D004268:DNA-Binding Proteins / Q000378:metabolism; D015723:Gene Library; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D051550:I-kappa B Kinase; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007372:Interferons / Q000378:metabolism*; D008954:Models, Biological; D008957:Models, Genetic; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism; D020218:Response Elements; D029082:Sendai virus / Q000235:genetics; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D020798:Two-Hybrid System Techniques
D033942:Adaptor Proteins, Vesicular Transport; D053181:Caspase 8; D020169:Caspases; D004268:DNA-Binding Proteins; D051550:I-kappa B Kinase; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007372:Interferons; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D048029:TNF Receptor-Associated Factor 6; D014157:Transcription Factors; C494232:IRF3 protein, human; C494234:IRF7 protein, human; C476286:Ticam1 protein, mouse; C403191:TBK1 protein, human; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C505530:CASP8 protein, human; C505526:Casp8 protein, mouse