TAG, a splice variant of the adaptor TRAM, negatively regulates the adaptor MyD88-independent TLR4 pathway

被引：113

作者：

Palsson-McDermott, Eva M. ^{[1
]}

Doyle, Sarah L. ^{[1
]}

McGettrick, Anne F. ^{[1
]}

Hardy, Matthew ^{[2
]}

Husebye, Harald ^{[3
]}

Banahan, Kathy ^{[1
]}

Gong, Mei ^{[4
]}

Golenbock, Douglas ^{[4
]}

Espevik, Terje ^{[3
]}

O'Neill, Luke A. J. ^{[1
]}

机构：

[1] Univ Dublin Trinity Coll, Sch Biochem & Immunol, Dublin 2, Ireland

[2] CSL, Parkville, Vic, Australia

[3] Norwegian Univ Sci & Technol, Inst Canc Res & Mol Med, N-7034 Trondheim, Norway

[4] Univ Massachusetts, Sch Med, Worcester, MA USA

来源：

NATURE IMMUNOLOGY | 2009年 / 10卷 / 06期

基金：

爱尔兰科学基金会;

关键词：

NF-KAPPA-B; RECEPTOR; TOLL-LIKE-RECEPTOR-4; LIPOPOLYSACCHARIDE; ACTIVATION; RECRUITMENT; MOLECULE; FAMILY;

D O I：

10.1038/ni.1727

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：579 / U30

页数：9

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