Gene interactions and pathways from curated databases and text-mining
Proc Natl Acad Sci U S A 2004, PMID: 14982987

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

Jiang, Zhengfan; Mak, Tak W; Sen, Ganes; Li, Xiaoxia

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.

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Text Mining Data

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

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

IRF3 → TLR3: " ( ii ) Are TRAF6, TAK1, and TAB2 also required for TLR3 mediated IRF3 activation ? "

IRF3 → TRAF6: " ( ii ) Are TRAF6 , TAK1, and TAB2 also required for TLR3 mediated IRF3 activation ? "

IRF3 → TAB2: " ( ii ) Are TRAF6, TAK1, and TAB2 also required for TLR3 mediated IRF3 activation ? "

IRF3 → TAK1: " ( ii ) Are TRAF6, TAK1 , and TAB2 also required for TLR3 mediated IRF3 activation ? "

IRF3 → TLR3: " 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 "

NF-kappaB → TLR3: " 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 "

IRF3 → 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 "

NF-kappaB → 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 "

IRF3 ⊣ DN-TRAF6: " In support of this finding, we showed that DN-TRAF6 and DN-TAK1 blocked poly ( I.C ) -induced NF-kappaB but not IRF3 activation "

IRF3 ⊣ DN-TAK1: " In support of this finding, we showed that DN-TRAF6 and DN-TAK1 blocked poly ( I.C ) -induced NF-kappaB but not IRF3 activation "

IRF3 → NF-kappaB: " In support of this finding, we showed that DN-TRAF6 and DN-TAK1 blocked poly ( I.C ) -induced NF-kappaB but not IRF3 activation "

Manually curated Databases

  • IRef Biogrid Interaction: TICAM1 — TRAF6 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: TICAM1 — TRAF5 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: TRAF2 — TICAM1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: TICAM1 — TLR3 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: TICAM1 — TRAF3 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: TRAF1 — TICAM1 (physical association, affinity chromatography technology)
  • IRef Hprd Interaction: TICAM1 — TRAF6 (in vivo)
  • IRef Hprd Interaction: TICAM1 — TRAF6 (two hybrid)
  • IRef Hprd Interaction: TICAM1 — TLR3 (two hybrid)
  • IRef Hprd Interaction: TICAM1 — TLR3 (in vivo)
In total, 6 gene pairs are associated to this article in curated databases