IRAK-2 participates in multiple toll-like receptor signaling pathways to NFκB via activation of TRAF6 ubiquitination
IRAK-2 participates in multiple toll-like receptor signaling pathways to NFκB via activation of TRAF6 ubiquitination
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DOI：
10.1074/jbc.m705266200
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发表时间：
2007-11-16
影响因子：
4.8
通讯作者：
Bowie, Andrew G.
中科院分区：
文献类型：
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作者：
Keating, Sinead E.;Maloney, Geraldine M.;Bowie, Andrew G.
已知 Toll 样受体 (TLR) 信号传导涉及白细胞介素 1 受体相关激酶 (IRAK)，但 IRAK-2 的具体作用仍不清楚。此外，尽管 IRAK-1 最初被认为是 TLR-NF kappa B 信号轴的核心，但最近的数据表明，它对于某些 TLR 的 NF kappa B 激活是可有可无的，并证明了它在干扰素调节因子激活中的替代作用。在这里，我们表明 IRAK-2 对于 TLR 介导的 NF kappa B 激活途径至关重要。痘病毒 TLR 拮抗剂 A52 通过与 IRAK-2 相互作用，抑制 TLR2、-3、-4、-5、-7 和 -9 配体对 NF kappa B 的激活，同时不影响干扰素调节因子的激活。通过小干扰 RNA 敲低 IRAK-2 表达，可抑制人细胞系中 TLR3、TLR4 和 TLR8 向 NF kappa B 发出的信号，更重要的是，抑制人原代细胞中 TLR4 介导的趋化因子产生。不同 TLR 对 IRAK-2 的使用是不同的，因为它作用于 TLR 接头 MyD88 和 Mal 的下游，但作用于 TRIF 的上游。 IRAK-2（而非 IRAK-1）的表达导致 TRAF6 泛素化，这是 NF kappa B 激活的关键事件。此外，IRAK-2 功能丧失突变体不能激活 NF kappa B，也不能促进 TRAF6 泛素化。因此，我们认为IRAK-2在TLR信号传导至NF kappa B中比IRAK-1发挥更重要的作用。
Toll-like receptor (TLR) signaling is known to involve interleukin-1 receptor-associated kinases (IRAKs), however the particular role of IRAK-2 has remained unclear. Further, although IRAK-1 was originally thought to be central for the TLR-NF kappa B signaling axis, recent data have shown that it is dispensable for NF kappa B activation for some TLRs and demonstrated an alternative role for it in interferon regulatory factor activation. Here we show that IRAK-2 is critical for the TLR-mediated NF kappa B activation pathway. The poxviral TLR antagonist A52 inhibited NF kappa B activation by TLR2, -3, -4, -5, -7, and -9 ligands, via its interaction with IRAK-2, while not affecting interferon regulatory factor activation. Knockdown of IRAK-2 expression by small interfering RNA suppressed TLR3, TLR4, and TLR8 signaling to NF kappa B in human cell lines, and importantly, TLR4-mediated chemokine production in primary human cells. IRAK-2 usage by different TLRs was distinct, because it acted downstream of the TLR adaptors MyD88 and Mal but upstream of TRIF. Expression of IRAK-2, but not IRAK-1, led to TRAF6 ubiquitination, an event critical for NF kappa B activation. Further, IRAK-2 loss-of-function mutants, which could not activate NF kappa B, were incapable of promoting TRAF6 ubiquitination. Thus we propose that IRAK-2 plays a more central role than IRAK-1 in TLR signaling to NF kappa B.