The myristoylation of TRIF-related adaptor molecule is essential for Toll-like receptor 4 signal transduction
The myristoylation of TRIF-related adaptor molecule is essential for Toll-like receptor 4 signal transduction
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DOI：
10.1073/pnas.0510041103
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发表时间：
2006-04-18
影响因子：
11.1
通讯作者：
Golenbock, DT
中科院分区：
文献类型：
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作者：
Rowe, DC;McGettrick, AF;Golenbock, DT
TRIF相关衔接子分子（TRAM）是第四个待描述的参与Toll样受体（TLR）信号传导的含有Toll/IL-1抗性结构域的衔接子。TRAM仅在TLR 4通路中起作用。在这里，我们通过共聚焦显微镜显示，TRAM定位在质膜和高尔基体，在那里它与TLR 4共定位。TRAM的膜定位是豆蔻酰化的结果，因为TRAM中预测的豆蔻酰化位点（TRAM-G2 A）的突变导致TRAM从膜上解离并重新定位到胞质溶胶中。此外，在体内用[H-3]肉豆蔻酸酯放射性标记TRAM，而不是TRAM-G2 A。与野生型TRAM不同，TRAM-G2 A的过表达未能引起IFN调节因子3或NF-κ B信号传导。此外，TRAM-G2 A不能在来自TRAM缺陷小鼠的骨髓来源的巨噬细胞中重建LPS应答。这些观察结果提供了明确的证据表明，肉豆蔻酰化的TRAM靶向质膜，在那里它是必要的LPS反应通过TLR 4信号转导途径，并提出了迄今为止未认识到的方式，其中LPS反应可以被调节。
TRIF-related adaptor molecule (TRAM) is the fourth Toll/IL-1 resistance domain-containing adaptor to be described that participates in Toll-like receptor (TLR) signaling. TRAM functions exclusively in the TLR4 pathway. Here we show by confocal microscopy that TRAM is localized in the plasma membrane and the Golgi apparatus, where it colocalizes with TLR4. Membrane localization of TRAM is the result of myristoylation because mutation of a predicted myristoylation site in TRAM (TRAM-G2A) brought about dissociation of TRAM from the membrane and its relocation to the cytosol. Further, TRAM, but not TRAM-G2A, was radiolabeled with [H-3]myristate in vivo. Unlike wild-type TRAM, overexpression of TRAM-G2A failed to elicit either IFN regulatory factor 3 or NF-kappa B signaling. Moreover, TRAM-G2A was unable to reconstitute LPS responses in bone marrow-derived macrophages from TRAM-deficient mice. These observations provide clear evidence that the myristoylation of TRAM targets it to the plasma membrane, where it is essential for LPS responses through the TLR4 signal transduction pathway, and suggest a hitherto unappreciated manner in which LPS responses can be regulated.