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-κB by the TLR3 ligand double-stranded RNA is Trif dependent. Here we investigated the 'downstream' signaling events that regulate TLR3-dependent Trif-induced NF-κB 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-κB, but not the kinase JNK or interferon-β, were abolished, suggesting that RIP1 mediates Trif-induced NF-κB activation. In contrast, the presence of RIP3 negatively regulated the Trif-RIP1–induced NF-κB pathway. Therefore, in contrast to other TLRs, which use interleukin 1 receptor-associated kinase (IRAK) proteins to activate NF-κB, TLR 3-induced NF-κB activation is dependent on RIP kinases.
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We thank S. Hertig, N. Olivos, H. Everett, L. Agostini, M. Thome and B. Beutler for technical support, constructs and discussions. Supported by the Swiss National Science Foundation and Commission of Technology and Innovation.
The authors declare no competing financial interests.
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Meylan, E., Burns, K., Hofmann, K. et al. RIP1 is an essential mediator of Toll-like receptor 3–induced NF-κB activation. Nat Immunol 5, 503–507 (2004). https://doi.org/10.1038/ni1061
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