TLR4信号从质膜上的TIRAP-MyD88介导的信号途径转换为内涵体TRAM-TRIF 介导的信号途径。来自英国伦敦大学的Vanhaesebroeck及其同事发现细胞需要磷脂酰肌醇-3激酶(PI(3)K)的异构体p110δ来完成Toll样受体(TLR4)的内化和含TIR结构域的接头蛋白(TIRAP)的降解。

-2012年11月《自然-免疫》

中文翻译


【题目】PI(3)K激酶的p110δ异构体控制TLR4信号的亚细胞区室化并保护机体免受内毒素休克

【译文】 脂多糖借助Toll样受体4(TLR4)通过TIRAP-MyD88和TRAM-TRIF适配体复合物分别激活质膜信号和内涵体信号,但是不清楚地是这些相互协调的不同细胞区室之间的信号如何转换。本研究在树突细胞中发现,磷脂酰肌醇-3激酶(PI(3)K)的异构体p110δ在质膜上诱导了TLR4的内化和含TIR结构域的接头蛋白(TIRAP)的分离,随后钙蛋白酶介导TIRAP的降解。因此,p110δ的失活延长了来自质膜的TIRAP介导的信号,从而提高了促炎细胞因子的分泌,然而,TRAM依赖的产生抗炎性细胞因子(白介素10和干扰素β)的内涵体信号却下降了。与改变的信号输出一致的是,p110δ缺陷小鼠更容易发生内毒素诱导的死亡。总之,通过控制TLR4信号复合物的拓扑结构,p110δ平衡TLR4信号途径中的所有内稳态。

英文原稿


[Title]: The p110δ isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock

[Authors]: Ezra Aksoy, Salma Taboubi, David Torres, Sandrine Delbauve, Abderrahman Hachani, Maria A Whitehead, Wayne P Pearce, Inma Berenjeno-Martin, Gemma Nock, Alain Filloux, Rudi Beyaert, Veronique Flamand & Bart Vanhaesebroeck  

[Abstract]: Lipopolysaccharide activates plasma-membrane signaling and endosomal signaling by Toll-like receptor 4 (TLR4) through the TIRAP-MyD88 and TRAM-TRIF adaptor complexes, respectively, but it is unclear how the signaling switch between these cell compartments is coordinated. In dendritic cells, we found that the p110δ isoform of phosphatidylinositol-3-OH kinase (PI(3)K) induced internalization of TLR4 and dissociation of TIRAP from the plasma membrane, followed by calpain-mediated degradation of TIRAP. Accordingly, inactivation of p110δ prolonged TIRAP-mediated signaling from the plasma membrane, which augmented proinflammatory cytokine production while decreasing TRAM-dependent endosomal signaling that generated anti-inflammatory cytokines (interleukin 10 and interferon-β). In line with that altered signaling output, p110δ-deficient mice showed enhanced endotoxin-induced death. Thus, by controlling the ‘topology’ of TLR4 signaling complexes, p110δ balances overall homeostasis in the TLR4 pathway.

原文地址

http://www.nature.com/ni/journal/v13/n11/abs/ni.2426.html

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本文链接: http://www.bioku.cn/201212/nature-immunology-pi3k-p110%ce%b4-isoform-tlr4-compartmentalization-signaling-endotoxic-shock/
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