TRAM is involved in IL-18 signaling and functions as a sorting adaptor for MyD88.
MyD88, a Toll/interleukin-1 receptor homology (TIR) domain-containing adaptor protein, mediates signals from the Toll-like receptors (TLR) or IL-1/IL-18 receptors to downstream kinases. In MyD88-dependent TLR4 signaling, the function of MyD88 is enhanced by another TIR domain-containing adaptor, Mal/TIRAP, which brings MyD88 to the plasma membrane and promotes its interaction with the cytosolic region of TLR4. Hence, Mal is recognized as the "sorting adaptor" for MyD88. In this study, a direct interaction between MyD88-TIR and another membrane-sorting adaptor, TRAM/TICAM-2, was demonstrated in vitro. Cell-based assays including RNA interference experiments and TRAM deficient mice revealed that the interplay between MyD88 and TRAM in cells is important in mediating IL-18 signal transduction. Live cell imaging further demonstrated the co-localized accumulation of MyD88 and TRAM in the membrane regions in HEK293 cells. These findings suggest that TRAM serves as the sorting adaptor for MyD88 in IL-18 signaling, which then facilitates the signal transduction. The binding sites for TRAM are located in the TIR domain of MyD88 and actually overlap with the binding sites for Mal. MyD88, the multifunctional signaling adaptor that works together with most of the TLR members and with the IL-1/IL-18 receptors, can interact with two distinct sorting adaptors, TRAM and Mal, in a conserved manner in a distinct context.
Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan. ohnishih@gifu-u.ac.jp
Hidenori
H
Ohnishi
Hidehito
H
Tochio
Zenichiro
Z
Kato
Norio
N
Kawamoto
Takeshi
T
Kimura
Kazuo
K
Kubota
Takahiro
T
Yamamoto
Tatsuyoshi
T
Funasaka
Hiroshi
H
Nakano
Richard W
RW
Wong
Masahiro
M
Shirakawa
Naomi
N
Kondo
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology; D053728:Interleukin-18 Receptor beta Subunit / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008958:Models, Molecular; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D053724:Receptors, Interleukin-18 / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C115629:IL18RAP protein, human; D020382:Interleukin-18; D053728:Interleukin-18 Receptor beta Subunit; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; D053724:Receptors, Interleukin-18; C480228:TICAM2 protein, human; C434984:TIRAP protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D018664:Interleukin-12; D007371:Interferon-gamma