MYD88, AN ADAPTER PROTEIN INVOLVED IN INTERLEUKIN-1 SIGNALING

MyD88 has a modular organization, an N-terminal death domain (DD) rela ted to the cytoplasmic signaling domains found in many members of the tumor necrosis factor receptor (TNF-R) superfamily, and a C-terminal T oll domain similar to that found in the expanding family of Toll/inter leukin-1-like receptors (IL-1R). This dual domain structure, together with the following observations, supports a role for MyD88 as an adapt er in IL-1 signal transduction; MyD88 forms homodimers in vivo through DD-DD and Toll-Toll interactions. Overexpression of MyD88 induces act ivation of the c-Jun N-terminal kinase (JNK) and the transcription fac tor NF-kappa B through its DD, A point mutation in MyD88, MyD88-1pr (F 56N), 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 I L-1-induced NF-kappa B activation. Overexpression of MyD88-1pr or MyD8 8-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 I L-1R, MyD88 coimmunoprecipitates with the IL-1R signaling complex in a n IL-1-dependent manner.