Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4.
Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4.
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抑制白介素1受体/TOLL样受体信号传导通过剪接的短形式的MyD88抑制是由于其未能募集IRAK-4所致。
DOI：
10.1084/jem.20021790
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发表时间：
2003-01-20
影响因子：
15.3
通讯作者：
Tschopp, J
中科院分区：
文献类型：
--
作者：
Burns, K;Janssens, S;Brissoni, B;Olivos, N;Beyaert, R;Tschopp, J
toll样受体（TLRs）和促炎白细胞介素1受体（IL-1R）家族成员依赖于MyD88的存在来进行有效的信号转导。MyD88 （n端死亡结构域[DD]和cooh端Toll/IL-1受体[TIR]结构域）的双体性质允许它将IL-1R/TLR的TIR结构域与称为IL-1R相关激酶(IRAK)-1的丝氨酸/苏氨酸激酶的DD连接起来。这触发IRAK-1磷酸化，进而激活多种信号级联反应，如转录因子核因子-κB的激活。相反，MyD88短链（MyD88s）的表达会导致IL-1/脂多糖诱导的NF-κB活化的关闭。MyD88s是MyD88的一种选择性剪接形式，只缺乏分隔DD和TIR结构域的短中间结构域。在这里，我们为这种差异提供分子解释。MyD88与IRAK-4有强烈的相互作用，IRAK-4是一种新发现的IL-1R/TLR信号通路必需的激酶。在MyD88s存在下，IRAK-1不会磷酸化，也不会激活NF-κB，也不会泛素化。因此，myd88作为IL-1R/TLR/ myd88触发信号的负调控因子，导致先天免疫应答的转录控制负调控。
Toll-like receptors (TLRs) and members of the proinflammatory interleukin 1 receptor (IL-1R) family are dependent on the presence of MyD88 for efficient signal transduction. The bipartite nature of MyD88 (N-terminal death domain [DD] and COOH-terminal Toll/IL-1 receptor [TIR] domain) allows it to link the TIR domain of IL-1R/TLR with the DD of the Ser/Thr kinase termed IL-1R–associated kinase (IRAK)-1. This triggers IRAK-1 phosphorylation and in turn the activation of multiple signaling cascades such as activation of the transcription factor nuclear factor (NF)-κB. In contrast, expression of MyD88 short (MyD88s), an alternatively spliced form of MyD88 that lacks only the short intermediate domain separating the DD and TIR domains, leads to a shutdown of IL-1/lipopolysaccharide-induced NF-κB activation. Here, we provide the molecular explanation for this difference. MyD88 but not MyD88s strongly interacts with IRAK-4, a newly identified kinase essential for IL-1R/TLR signaling. In the presence of MyD88s, IRAK-1 is not phosphorylated and neither activates NF-κB nor is ubiquitinated. Thus, MyD88s acts as a negative regulator of IL-1R/TLR/MyD88-triggered signals, leading to a transcriptionally controlled negative regulation of innate immune responses.
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