MyD88-induced downregulation of IRAK-4 and its structural requirements
MyD88-induced downregulation of IRAK-4 and its structural requirements
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DOI：
10.1111/j.1574-695x.2008.00425.x
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发表时间：
2008-07-01
影响因子：
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通讯作者：
Tanamoto, Ken-ichi
中科院分区：
文献类型：
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作者：
Hatao, Fumihiko;Yamamoto, Maya;Tanamoto, Ken-ichi
IRAK-4 在 Toll 样受体 (TLR)/IL-1 受体信号转导中发挥重要作用。然而，其信号传导和调节机制仍然难以捉摸。我们之前曾报道过，刺激 TLR2、TLR4 或 TLR9（而非 TLR3）会导致 IRAK-4 蛋白下调。在这里，我们发现 MyD88 的表达导致 HEK293 细胞中内源性和外源性表达的 IRAK-4 蛋白下调。 TRIF 的表达虽然诱导 NF-κ B 激活，但不会引起 IRAK-4 下调。缺少死亡结构域的 MyD88 缺失突变体或 MyD88 的表达（两者均不诱导 NF-κ B 激活）不会导致 IRAK-4 下调。在缺乏激酶结构域的 IRAK-4 突变体中观察到 MyD88 诱导的下调，但在另一个缺乏死亡结构域的突变体中则没有观察到。这些结果表明，IRAK-4 的下调需要激活 MyD88 依赖性途径，并且 MyD88 和 IRAK-4 的死亡结构域对于这种下调很重要。
IRAK-4 plays an essential role in Toll-like receptor (TLR)/IL-1 receptor signaling. However, its signaling and regulation mechanisms have remained elusive. We have reported previously that stimulation of TLR2, TLR4 or TLR9, but not TLR3, leads to downregulation of IRAK-4 protein. Here, we show that expression of MyD88 leads to downregulation of endogenous as well as exogenously expressed IRAK-4 protein in HEK293 cells. Expression of TRIF did not cause IRAK-4 downregulation although it induced NF-kappa B activation. Expression of either a deletion mutant of MyD88 lacking its death domain or MyD88s, neither of which induced NF-kappa B activation, did not lead to IRAK-4 downregulation. MyD88-induced downregulation was observed in an IRAK-4 mutant lacking the kinase domain, but not in another mutant lacking the death domain. These results demonstrate that downregulation of IRAK-4 requires activation of the MyD88-dependent pathway and that the death domains of both MyD88 and IRAK-4 are important for this downregulation.