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RIP1 is an essential mediator of Toll-like receptor 3-induced NF-kappa B activation.
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Stimulation of Toll-like receptors (TLRs) initiates potent innate immune responses through Toll-interleukin 1 receptor (TIR) domain-containing adaptors such as MyD88 and Trif. Analysis of Trif-deficient mice has shown that TLR3-dependent activation of the transcription factor NF-kappa B by the TLR3 ligand double-stranded RNA is Trif dependent. Here we investigated the 'downstream' signaling events that regulate TLR3-dependent Trif-induced NF-kappa B activation. Trif recruited the kinases receptor interacting protein (RIP)-1 and RIP3 through its RIP homotypic interaction motif. In the absence of RIP1, TLR3-mediated signals activating NF-kappa B, but not the kinase JNK or interferon-beta, were abolished, suggesting that RIP1 mediates Trif-induced NF-kappa B activation. In contrast, the presence of RIP3 negatively regulated the Trif-RIP1-induced NF-kappa B pathway. Therefore, in contrast to other TLRs, which use interleukin 1 receptor-associated kinase (IRAK) proteins to activate NF-kappa B, TLR 3-induced NF-kappa B activation is dependent on RIP kinases.
Adaptor Proteins, Vesicular Transport/genetics, Adaptor Proteins, Vesicular Transport/metabolism, Animals, Humans, Membrane Glycoproteins/genetics, Membrane Glycoproteins/metabolism, Mice, NF-kappa B/metabolism, Proteins/genetics, Proteins/metabolism, Receptor-Interacting Protein Serine-Threonine Kinases, Receptors, Cell Surface/genetics, Receptors, Cell Surface/metabolism, Toll-Like Receptor 3, Toll-Like Receptors, Transfection
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