Burns K, Martinon F, Esslinger C, Pahl H, Schneider P, Bodmer J L, Di Marco F, French L, Tschopp J
Institute of Biochemistry, Lausanne Branch, University of Lausanne, Switzerland.
J Biol Chem. 1998 May 15;273(20):12203-9. doi: 10.1074/jbc.273.20.12203.
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-kappaB through its DD. A point mutation in MyD88, MyD88-lpr (F56N), which prevents dimerization of the DD, also blocks induction of these activities. MyD88-induced NF-kappaB activation is inhibited by the dominant negative versions of TRAF6 and IRAK, which also inhibit IL-1-induced NF-kappaB activation. Overexpression of MyD88-lpr or MyD88-Toll (expressing only the Toll domain) acted to inhibit IL-1-induced NF-kappaB and JNK activation in a 293 cell line overexpressing the IL-1RI. MyD88 coimmunoprecipitates with the IL-1R signaling complex in an IL-1-dependent manner.
髓样分化因子88（MyD88）具有模块化结构，其N端死亡结构域（DD）与肿瘤坏死因子受体（TNF-R）超家族许多成员中发现的细胞质信号结构域相关，C端Toll结构域与Toll样受体/白细胞介素-1样受体（IL-1R）不断扩大的家族中发现的结构域相似。这种双结构域结构，连同以下观察结果，支持MyD88作为IL-1信号转导中的衔接蛋白发挥作用；MyD88在体内通过DD-DD和Toll-Toll相互作用形成同二聚体。MyD88的过表达通过其DD诱导c-Jun N端激酶（JNK）和转录因子NF-κB的激活。MyD88中的一个点突变，即MyD88-lpr（F56N），可阻止DD的二聚化，也会阻断这些活性的诱导。MyD88诱导的NF-κB激活受到TRAF6和IRAK显性负性变体的抑制，这些变体也抑制IL-1诱导的NF-κB激活。在过表达IL-1RI的293细胞系中，MyD88-lpr或MyD88-Toll（仅表达Toll结构域）的过表达可抑制IL-1诱导的NF-κB和JNK激活。MyD88以IL-1依赖的方式与IL-1R信号复合物共免疫沉淀。
