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.
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
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
Proc. Natl. Acad. Sci. U.S.A.
Date: Mar. 09, 2004
PubMed ID: 14982987
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