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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The myristoylation of TRIF-related adaptor molecule is essential for Toll-like receptor 4 signal transduction
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The myristoylation of TRIF-related adaptor molecule is essential for Toll-like receptor 4 signal transduction

机译：TRIF相关衔接子分子的肉豆蔻酰化对于Toll样受体4信号转导至关重要

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摘要

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.
机译：TRIF相关衔接子分子（TRAM）是第四个包含Toll / IL-1抗性域的衔接子，参与Toll样受体（TLR）信号传导。 TRAM仅在TLR4路径中起作用。在这里，我们通过共聚焦显微镜显示，TRAM位于质膜和高尔基体中，与TLR4共定位。 TRAM的膜定位是肉豆蔻酰化的结果，因为TRAM中预测的肉豆蔻酰化位点（TRAM-G2A）发生突变导致TRAM从膜上解离，并重新定位到细胞质中。此外，在体内用[H-3]肉豆蔻酸酯对TRAM而非TRAM-G2A进行了放射性标记。与野生型TRAM不同，TRAM-G2A的过表达未能引起IFN调节因子3或NF-κB信号传导。此外，TRAM-G2A无法重建来自TRAM缺陷小鼠的骨髓巨噬细胞中的LPS反应。这些观察结果提供了明确的证据，表明TRAM的肉豆蔻酰化将其靶向质膜，在质膜上它是通过TLR4信号转导途径进行LPS反应所必需的，并暗示了迄今为止从未理解的可以调节LPS反应的方式。

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