Toll-like receptor 3-mediated activation of NF-κB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing INF-β
Toll-like receptor 3-mediated activation of NF-κB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing INF-β
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DOI：
10.1073/pnas.0308496101
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发表时间：
2004-03-09
影响因子：
11.1
通讯作者：
Li, XX
中科院分区：
文献类型：
--
作者：
Jiang, ZF;Mak, TW;Li, XX
我们之前已经证明，双链RNA触发的Toll样受体3（TLR 3）介导的信号传导不依赖于MyD 88，IRAK 4和IRAK。相反，TRAF 6、TAK 1和TAB 2在poly（I-C）刺激时被募集到TLR 3。TRAF 6-TAK 1-TAB 2随后被转运至胞质溶胶，在胞质溶胶中TAK 1被磷酸化并活化，导致IkappaB激酶和NF κ B活化。本研究解决了两个重要问题：（i）TRAM TAK 1和TAB 2如何被招募到TLR 3？(it)TRAF 6、TAK 1和TAB 2也是TLR 3介导的IRF 3激活所必需的吗？最近，一种新的含有Toll-IL-1受体（TIR）的衔接子，含有TIR结构域的诱导IFN-β的衔接子（TRIF），被证明在TLR 3介导的NF-κ B和IRF 3的活化中起关键作用。我们发现TLR 3通过TRIF中的TRAF 6结合序列（PEEMSW，氨基酸250-255）经由衔接子TRIF募集TRAM。该TRAF 6结合序列的突变消除了TRIF与TRAF 6的相互作用，但不与TLR 3的相互作用。有趣的是，TRIF的TRAF 6结合位点的突变仅消除了其激活NF-κ B的能力，而不是IRF 3，这表明TLR 3介导的NF-κ B和IRF 3的激活可能在TRIF处分叉。为了支持这一发现，我们发现DN-TRAF 6和DN-TAK 1阻断了poly（I-C）诱导的NF-κ B而不是IRF 3激活。此外，尽管poly（I-C）诱导的NF-κ B活化在TRAF 6-/- MEFs中完全消除，但信号诱导的IRF 3活化是TRAF 6独立的。总之，TRIF通过其TRAF 6结合位点将TRAF 6-TAK 1-TAB 2募集到TLR 3，这是NF-κ B而不是IRF 3活化所需的。因此，双链RNA诱导的TLR 3/TRIF介导的NF-κ B和IRF 3激活在TRIF处发散。
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 TRAM TAK1, and TAB2 recruited to TLR3? (it) 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 TRAM 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.