Epithelial barrier dysfunction and cell migration induction via JNK/cofilin/actin by angubindin-1
Epithelial barrier dysfunction and cell migration induction via JNK/cofilin/actin by angubindin-1
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DOI：
10.1080/21688370.2019.1695475
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发表时间：
2020-01-02
期刊：
影响因子：
3.1
通讯作者：
Kojima, Takashi
中科院分区：
文献类型：
--
作者：
Konno, Takumi;Kohno, Takayuki;Kojima, Takashi
Angulin-1/LSR 是一种三细胞紧密连接分子，在维持上皮和内皮屏障方面发挥着重要作用。三细胞接触处的肌动蛋白细胞骨架也有助于维持上皮屏障。 angulin-1/LSR 的缺失会增强各种癌细胞的迁移。 Angubindin-1 是 angulin-1/LSR 和 angulin-3 的新型结合剂。它是由产气荚膜梭菌 iota 毒素的 angulin-1 结合位点产生的肽，影响肌动蛋白细胞骨架并降低上皮和内皮屏障功能。然而，其调控机制尚不清楚。为了研究angubindin-1对上皮屏障功能障碍和细胞迁移诱导的调节机制，我们使用具有高LSR表达和上皮屏障功能的人子宫内膜癌细胞系Sawano。 Angubindin-1 降低 LSR 表达和上皮屏障功能并增加细胞迁移。它抑制钙开关模型中上皮屏障功能的恢复。在三细胞接触处，膜的下沉和连接处附近肌动蛋白纤维的增加是由 angubindin-1 引起的。它在三细胞接触处动态地将 F-肌动蛋白从线状结构改变为点状结构。 Angubindin-1 短暂地增加了 cofilin 和 JNK 的磷酸化，它们参与细胞内肌动蛋白细胞骨架的调节。此外，JNK 和 JNK 抑制剂 SP600125 的敲低可防止 angubindin-1 诱导的上皮屏障功能下降和细胞迁移增加。这些发现表明 angubindin-1 可能通过 JNK/cofilin/actin 细胞骨架动力学可逆地调节三细胞接触处的上皮屏障和细胞迁移。
Angulin-1/LSR is a tricellular tight junction molecule, that plays an important role in maintaining the epithelial and endothelial barriers. The actin cytoskeleton at tricellular contacts also contributes to the maintenance of the epithelial barrier. Loss of angulin-1/LSR enhances the migration of various cancer cells. Angubindin-1 is a novel binder to angulin-1/LSR and angulin-3. It is a peptide generated from the angulin-1 binding site of Clostridium perfringens iota toxin, which affects the actin cytoskeleton and decreases the epithelial and endothelial barrier functions. However, its regulatory mechanisms are not well understood. To investigate the regulatory mechanisms of the epithelial barrier dysfunction and cell migration induction by angubindin-1, we used human endometrial cancer cell line Sawano, which has high LSR expression and the epithelial barrier function. Angubindin-1 decreased LSR expression and the epithelial barrier function and increased cell migration. It inhibited the recovery of the epithelial barrier function in a Ca-switch model. At tricellular contacts, sinking of the membrane and an increase of actin fibers near the junctions were caused by angubindin-1. It dynamically changed F-actin from lines to dot-like structures at tricellular contacts. Angubindin-1 transiently increased the phosphorylation of cofilin and JNK, which are involved in the regulation of the intracellular actin cytoskeleton. Furthermore, knockdown of JNK and the JNK inhibitor SP600125 prevented the decrease of the epithelial barrier function and the increase of cell migration induced by angubindin-1. These findings suggest that angubindin-1 might reversibly regulate the epithelial barrier and cell migration at tricellular contacts via JNK/cofilin/actin cytoskeleton dynamics.