CFTR in a lipid raft-TNFR1 complex modulates gap junctional intercellular communication and IL-8 secretion
CFTR in a lipid raft-TNFR1 complex modulates gap junctional intercellular communication and IL-8 secretion
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DOI：
10.1016/j.bbamcr.2008.01.007
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发表时间：
2008-05-01
影响因子：
5.1
通讯作者：
Chanson, Marc
中科院分区：
文献类型：
--
作者：
Dudez, Tecla;Borot, Florence;Chanson, Marc
囊性纤维化跨膜传导调节因子(CFTR)的突变在囊性纤维化(CF)患者的肺部引起慢性炎症反应。我们已经证明，通过Src家族酪氨酸激酶(SFK)传递的肿瘤坏死因子-α信号是有缺陷的，这是由于肿瘤坏死因子-α不能调节CF细胞中的缝隙连接通讯(GJIC)。在这里，我们试图在分子水平上阐明肿瘤坏死因子-α信号与CFTR功能之间的联系机制。在MDCKI上皮细胞模型中，表达野生型(WtCFTR)或缺乏PDZ相互作用基序的突变型(CFTR-Delta TRL)的MDCKI上皮细胞模型中，肿瘤坏死因子-α增加了耐洗涤剂膜微区(DRM)中WtCFTR的数量，但不增加CFTR-Delta TRL的数量。这种募集受到SFK活性的调节，并与DRM对TNFR1和c-Src的定位有关。激活TNFR1信号还可降低WtCFTR细胞的GJIC，并显著刺激IL-8的产生。相反，DRM中CFTR1的缺失与TNFR1信号的异常有关，表现为CFTRDelta TRL细胞中的TNFR1和c-Src没有被募集到脂筏上，并且失去了对GJIC和IL-8分泌的调节。这些结果表明，CFTR在脂筏中的定位与c-Src和TNFR1相关，为调节GJIC和细胞因子信号提供了一个响应的信号复合体。(C)2008爱思唯尔B.V.保留所有权利。
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause a chronic inflammatory response in the lung of patients with Cystic Fibrosis (CF). We have showed that TNF-alpha signaling through the Src family tyrosine kinases (SFKs) was defective as determined by an inability of TNF-alpha to regulate gap junctional communication (GJIC) in CF cells. Here, we sought to elucidate the mechanisms linking TNF-alpha signaling to the functions of CFTR at the molecular level. In a MDCKI epithelial cell model expressing wild-type (WtCFTR) or mutant CFTR lacking its PDZ-interacting motif (CFTR-Delta TRL), TNF-alpha increased the amount of WtCFTR but not CFTR-Delta TRL in detergent-resistant membrane microdomains (DRMs). This recruitment was modulated by SFK activity and associated with DRM localization of TNFR1 and c-Src. Activation of TNFR1 signaling also decreased GJIC and markedly stimulated IL-8 production in WtCFTR cells. In contrast, the absence of CFTR in DRMs was associated with abnormal TNFR1 signaling as revealed by no recruitment of TNFR1 and c-Src to lipid rafts in CFTR-Delta TRL cells and loss of regulation of GJIC and IL-8 secretion. These results suggest that localization of CFTR in lipid rafts in association with c-Src and TNFR1 provides a responsive signaling complex to regulate GJIC and cytokine signaling. (C) 2008 Elsevier B.V All rights reserved.