title: Two tyrosine residues of Toll-like receptor 3 trigger different steps of NF-kappa B activation.
abstract: Innate immune response to viral infection is often triggered by Toll-like receptor 3 (TLR3)-mediated signaling by double-stranded (ds) RNA, which culminates in the activation of the transcription factor NF-kappaB and induction of NF-kappaB-driven genes. We demonstrated that dsRNA-induced phosphorylation of two specific tyrosine residues, 759 and 858, of TLR3 was necessary and sufficient for complete activation of the NF-kappaB pathway. When Tyr-759 of TLR3 was mutated, gene induction was inhibited, although NF-kappaB was partially activated. It was released from IkappaB and translocated to the nucleus but failed to bind to the kappaB site of the target A20 gene promoter. This defect could be attributed to incomplete phosphorylation of the RelA (p65) subunit of NF-kappaB, as revealed by two-dimensional gel analyses of p65, isolated from dsRNA-treated cells expressing either wild type TLR3 or the Tyr-759 --> Phe mutant TLR3. Thus, two phosphotyrosine residues of TLR3 activate two distinct pathways, one leading to NF-kappaB release and the other leading to its phosphorylation.
authors.affiliation: Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Saumendra N
authors.initials: SN
authors.lastname: Sarkar
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Elco
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Peters
authors.forename: Saurabh
authors.initials: S
authors.lastname: Chattopadhyay
authors.forename: Ganes C
authors.initials: GC
authors.lastname: Sen
mesh_terms: D002460:Cell Line; D004268:DNA-Binding Proteins; D015967:Gene Expression Regulation, Viral; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012330:RNA, Double-Stranded / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051196:Toll-Like Receptor 3 / Q000378:metabolism / Q000502:physiology*; D051996:Transcription Factor RelA / Q000378:metabolism; D015533:Transcriptional Activation; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014443:Tyrosine / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; C498143:RELA protein, human; D012330:RNA, Double-Stranded; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D051996:Transcription Factor RelA; D014443:Tyrosine; D051550:I-kappa B Kinase; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3