TAG, a splice variant of the adaptor TRAM, negatively regulates the adaptor MyD88-independent TLR4 pathway.
Toll-like receptor 4 (TLR4) signals the induction of transcription factor IRF3-dependent genes from the early endosome via the adaptor TRAM. Here we report a splice variant of TRAM, TAG ('TRAM adaptor with GOLD domain'), which has a Golgi dynamics domain coupled to TRAM's Toll-interleukin 1 receptor domain. After stimulation with lipopolysaccharide, TRAM and TAG localized to late endosomes positive for the GTPase Rab7a. TAG inhibited activation of IRF3 by lipopolysaccharide. Knockdown of TAG with small interfering RNA enhanced induction of the chemokine CCL5 (RANTES), but not of interleukin 8, by lipopolysaccharide in human peripheral blood mononuclear cells. TAG displaced the adaptor TRIF from TRAM. TAG is therefore an example of a specific inhibitor of the adaptor MyD88-independent pathway activated by TLR4. Targeting TAG could be useful in the effort to boost the immunostimulatory effect of TLR4 without causing unwanted inflammation.
School of Biochemistry and Immunology, Trinity College Dublin, Ireland.
Eva M
EM
Palsson-McDermott
Sarah L
SL
Doyle
Anne F
AF
McGettrick
Matthew
M
Hardy
Harald
H
Husebye
Kathy
K
Banahan
Mei
M
Gong
Douglas
D
Golenbock
Terje
T
Espevik
Luke A J
LA
O'Neill
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D018946:Chemokine CCL5 / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D013379:Substrate Specificity; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014162:Transfection; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C483024:CCL5 protein, human; D018946:Chemokine CCL5; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D020033:Protein Isoforms; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C470409:TICAM1 protein, human; C480228:TICAM2 protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D000090802:rab7 GTP-Binding Proteins; D020691:rab GTP-Binding Proteins