Multivalent Adhesion Molecule 7 Clusters Act as Signaling Platform for Host Cellular GTPase Activation and Facilitate Epithelial Barrier Dysfunction
Multivalent Adhesion Molecule 7 Clusters Act as Signaling Platform for Host Cellular GTPase Activation and Facilitate Epithelial Barrier Dysfunction
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DOI：
10.1371/journal.ppat.1004421
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发表时间：
2014-09-01
期刊：
影响因子：
6.7
通讯作者：
Krachler, Anne Marie
中科院分区：
文献类型：
--
作者：
Lim, Jenson;Stones, Daniel H.;Krachler, Anne Marie
副溶血性弧菌是一种新出现的细菌病原体，它在胃肠道中定植，可引起严重的肠炎和菌血症。在感染期间，副溶血性弧菌主要附着在小肠上，在小肠上引起广泛的组织损伤并破坏上皮屏障的完整性。我们之前已经描述了多价粘附分子（MAM） 7有助于副溶血性弧菌对上皮细胞的初始附着。本研究表明，细菌黏附素通过表面诱导的黏附素簇与宿主细胞膜磷脂酸脂质之间的多价相互作用，诱导宿主细胞中小GTPase RhoA的激活和肌动蛋白重排。在副溶血性弧菌的感染研究中，我们进一步证明了粘附素触发的ROCK/LIMK信号轴的激活足以重新分配紧密连接蛋白，导致上皮屏障功能的丧失。综上所述，这些发现揭示了一种前所未有的机制，即黏附素作为宿主细胞信号通路的组装平台，最终促进细菌病原体突破上皮屏障。
Vibrio parahaemolyticus is an emerging bacterial pathogen which colonizes the gastrointestinal tract and can cause severe enteritis and bacteraemia. During infection, V. parahaemolyticus primarily attaches to the small intestine, where it causes extensive tissue damage and compromises epithelial barrier integrity. We have previously described that Multivalent Adhesion Molecule (MAM) 7 contributes to initial attachment of V. parahaemolyticus to epithelial cells. Here we show that the bacterial adhesin, through multivalent interactions between surface-induced adhesin clusters and phosphatidic acid lipids in the host cell membrane, induces activation of the small GTPase RhoA and actin rearrangements in host cells. In infection studies with V. parahaemolyticus we further demonstrate that adhesin-triggered activation of the ROCK/LIMK signaling axis is sufficient to redistribute tight junction proteins, leading to a loss of epithelial barrier function. Taken together, these findings show an unprecedented mechanism by which an adhesin acts as assembly platform for a host cellular signaling pathway, which ultimately facilitates breaching of the epithelial barrier by a bacterial pathogen.