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

Nat Immunol. 2004 May;5(5):503-7. doi: 10.1038/ni1061. Epub 2004 Apr 4.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Adaptor Proteins, Vesicular Transport
  • Membrane Glycoproteins
  • NF-kappa B
  • Proteins
  • Receptors, Cell Surface
  • TICAM-1 protein, mouse
  • TICAM1 protein, human
  • TLR3 protein, human
  • Toll-Like Receptor 3
  • Toll-Like Receptors
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse