Trif-related adapter molecule is phosphorylated by PKCε during toll-like receptor 4 signaling
Trif-related adapter molecule is phosphorylated by PKCε during toll-like receptor 4 signaling
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DOI：
10.1073/pnas.0600462103
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发表时间：
2006-06-13
影响因子：
11.1
通讯作者：
O'Neill, Luke A. J.
中科院分区：
文献类型：
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作者：
McGettrick, Anne F.;Brint, Elizabeth K.;O'Neill, Luke A. J.
PKC epsilon已被证明在革兰氏阴性细菌产物LPS的作用中起关键作用；然而，PKC epsilon在LPS信号转导中的靶点尚不清楚。LPS信号转导是由Toll样受体4介导的，Toll样受体4使用四种接头蛋白，即MyD88、MyD88接头样(MAL)、含有Toll/IL-1R结构域的接头诱导干扰素-β(TRIF)和TRIF相关接头分子(TRAM)。在这里，我们证明了TRAM被丝氨酸-16上的PKC epsilon以内毒素依赖的方式瞬时磷酸化。在PKC epsilon缺陷细胞中，依赖于TRAM的干扰素调节因子3的激活和趋化因子RANTES的诱导都被减弱。TRAMS16A在过度表达时是不活跃的，并且在TRAM缺陷的细胞中重建信号的能力减弱。因此，我们发现了Toll样受体4信号转导的一个关键过程，将TRAM确定为PKC epsilon的靶标。
PKC epsilon has been shown to play a key role in the effect of the Gram-negative bacterial product LPS; however, the target for PKC epsilon in LPS signaling is unknown. LPS signaling is mediated by Toll-like receptor 4, which uses four adapter proteins, MyD88, MyD88 adapter-like (Mal), Toll/IL-1R domain-containing adapter inducing IFN-beta (Trif), and Trif-related adapter molecule (TRAM). Here we show that TRAM is transiently phosphorylated by PKC epsilon on serine-16 in an LPS-dependent manner. Activation of IFN regulatory factor 3 and induction of the chemokine RANTES, which are both TRAM-dependent, were attenuated in PKC epsilon-deficient cells. TRAMS16A is inactive when overexpressed and is attenuated in its ability to reconstitute signaling in TRAM-deficient cells. We have therefore uncovered a key process in Toll-like receptor 4 signaling, identifying TRAM as the target for PKC epsilon.