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Toll-like receptor 3-mediated activation of NF-kappaB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta.

We have previously shown that double-stranded RNA-triggered, Toll-like receptor 3 (TLR3)-mediated signaling is independent of MyD88, IRAK4, and IRAK. Instead, TRAF6, TAK1, and TAB2 are recruited to TLR3 on poly(I.C) stimulation. TRAF6-TAK1-TAB2 are then translocated to the cytosol where TAK1 is phosphorylated and activated, leading to the activation of IkappaB kinase and NFkappaB. The present study addressed two important questions: (i) How are TRAF6, TAK1, and TAB2 recruited to TLR3? (ii) Are TRAF6, TAK1, and TAB2 also required for TLR3-mediated IRF3 activation? Recently, a novel Toll-IL-1 receptor (TIR)-containing adapter, TIR domain-containing adapter inducing IFN-beta (TRIF), was shown to play a critical role in TLR3-mediated activation of NF-kappaB and IRF3. We found that TLR3 recruits TRAF6 via adapter TRIF through a TRAF6-binding sequence in TRIF (PEEMSW, amino acids 250-255). Mutation of this TRAF6-binding sequence abolished the interaction of TRIF with TRAF6, but not with TLR3. Interestingly, mutation of the TRAF6-binding site of TRIF only abolished its ability to activate NF-kappaB but not IRF3, suggesting that TLR3-mediated activation of NF-kappaB and IRF3 might bifurcate at TRIF. In support of this finding, we showed that DN-TRAF6 and DN-TAK1 blocked poly(I.C)-induced NF-kappaB but not IRF3 activation. Furthermore, whereas poly(I.C)-induced NF-kappaB activation is completely abolished inTRAF6-/- MEFs, the signal-induced activation of IRF3 is TRAF6 independent. In conclusion, TRIF recruits TRAF6-TAK1-TAB2 to TLR3 through its TRAF6-binding site, which is required for NF-kappaB but not IRF3 activation. Therefore, double-stranded RNA-induced TLR3/TRIF-mediated NF-kappaB and IRF3 activation diverge at TRIF.

Pubmed ID: 14982987


  • Jiang Z
  • Mak TW
  • Sen G
  • Li X


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

March 9, 2004

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM 600020

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Amino Acid Sequence
  • Animals
  • Antigens, Differentiation
  • Binding Sites
  • Cells, Cultured
  • DNA-Binding Proteins
  • HeLa Cells
  • Humans
  • Interferon Regulatory Factor-3
  • Interleukin-1 Receptor-Associated Kinases
  • Male
  • Membrane Glycoproteins
  • Models, Biological
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Protein Kinases
  • Proteins
  • RNA, Double-Stranded
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Signal Transduction
  • TNF Receptor-Associated Factor 6
  • Toll-Like Receptor 3
  • Toll-Like Receptors
  • Transcription Factors