RIP1 is an essential mediator of Toll-like receptor 3-induced NF-[kappa]B activation

• Published in: Nature immunology Vol. 5; no. 5; p. 503
• Main Authors: Meylan, Etienne, Burns, Kim, Hofmann, Kay, Blancheteau, Vincent, Martinon, Fabio, Kelliher, Michelle, Tschopp, Jürg
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group 01.05.2004
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni1061

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.