MyD88, an adapter protein involved in interleukin-1 signaling.
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.
Burns
K
K
Institute of Biochemistry, Lausanne Branch, University of Lausanne, Switzerland.
Martinon
F
F
Esslinger
C
C
Pahl
H
H
Schneider
P
P
Bodmer
J L
JL
Di Marco
F
F
French
L
L
Tschopp
J
J
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D019281:Dimerization; D004789:Enzyme Activation; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D011971:Receptors, Immunologic; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D007375:Interleukin-1; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011506:Proteins; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases