MyD88, an adapter protein involved in interleukin-1 signaling
MyD88, an adapter protein involved in interleukin-1 signaling
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DOI：
10.1074/jbc.273.20.12203
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发表时间：
1998-05-15
影响因子：
4.8
通讯作者：
Tschopp, J
中科院分区：
文献类型：
--
作者：
Burns, K;Martinon, F;Tschopp, J
MyD 88具有模块化组织，N-末端死亡结构域（DD）与肿瘤坏死因子受体（TNF-R）超家族的许多成员中发现的胞质信号传导结构域相关，并且C-末端Toll结构域类似于Toll/白介素-1样受体（IL-1 R）的扩展家族中发现的结构域。这种双结构域结构与以下观察结果一起支持MyD 88在IL-1信号转导中作为衔接子的作用; MyD 88通过DD-DD和Toll-Toll相互作用在体内形成同源二聚体。MyD 88的过表达通过MyD 88中的DD，A点突变MyD 88 - 1 pr（F56 N）诱导c-Jun N-末端激酶（JNK）和转录因子NF-κ B的活化，这阻止了DD的二聚化，也阻断了这些活性的诱导。MyD 88诱导的NF-κ B活化被TRAF 6和IRAK的显性负性形式抑制，TRAF 6和IRAK也抑制IL-1诱导的NF-κ B活化。在过表达IL-1 R的293细胞系中，MyD 88 - 1 pr或MyD 88-Toll（仅表达Toll结构域）的过表达可抑制IL-1诱导的NF-κ B和JNK活化，MyD 88以IL-1依赖性方式与IL-1 R信号传导复合物免疫共沉淀。
MyD88 has a modular organization, an N-terminal death domain (DD) related to the cytoplasmic signaling domains found in many members of the tumor necrosis factor receptor (TNF-R) superfamily, and a C-terminal Toll domain similar to that found in the expanding family of Toll/interleukin-1-like receptors (IL-1R). This dual domain structure, together with the following observations, supports a role for MyD88 as an adapter in IL-1 signal transduction; MyD88 forms homodimers in vivo through DD-DD and Toll-Toll interactions. Overexpression of MyD88 induces activation of the c-Jun N-terminal kinase (JNK) and the transcription factor NF-kappa B through its DD, A point mutation in MyD88, MyD88-1pr (F56N), which prevents dimerization of the DD, also blocks induction of these activities. MyD88-induced NF-kappa B activation is inhibited by the dominant negative versions of TRAF6 and IRAK, which also inhibit IL-1-induced NF-kappa B activation. Overexpression of MyD88-1pr or MyD88-Toll (expressing only the Toll domain) acted to inhibit IL-1-induced NF-kappa B and JNK activation in a 293 cell line overexpressing the IL-1R, MyD88 coimmunoprecipitates with the IL-1R signaling complex in an IL-1-dependent manner.