A role for myosin IXb, a motor-RhoGAP chimera, in epithelial wound healing and tight junction regulation.
A role for myosin IXb, a motor-RhoGAP chimera, in epithelial wound healing and tight junction regulation.
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DOI：
10.1091/mbc.e11-09-0803
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发表时间：
2012-07
影响因子：
3.3
通讯作者：
Mooseker MS
中科院分区：
文献类型：
--
作者：
Chandhoke SK;Mooseker MS
Myo 9 b是一种与炎症性肠病有关的马达-RhoGAP嵌合体。研究结果表明，Myo 9 b在集体和个体伤口诱导的细胞迁移过程中是必不可少的。这对于保持紧密结势垒完整性也很重要。编码肌球蛋白IXb重链（Myo 9 b）的基因多态性与几种形式的炎症性肠病（IBD）有关。鉴于Myo 9 b在其尾部含有RhoGTP酶激活蛋白结构域，它可能在Rho介导的肌动蛋白细胞骨架修饰中发挥关键作用，这对肠道屏障功能至关重要。在肠上皮细胞系Caco 2BBe（BBe）的受伤单层中，Myo 9 b定位于迁移细胞的板状伪足的最前沿。表现出Myo 9 b表达缺失的BBe细胞缺乏板状伪足，不能迁移到伤口中，并且在面向伤口的细胞的自由边缘处形成肌动蛋白的应力纤维样阵列。这些细胞还表现出紧密连接（TJ）蛋白定位的破坏，包括ZO-1、闭合蛋白和封闭蛋白-1。在表达DN-尾尖的细胞中，对右旋糖酐的扭转运动性和连接通透性大大增加。有趣的是，这种效应传播到相邻细胞。与Myo 9 b在调节活性Rho水平中的作用一致，RhoGTP和肌球蛋白轻链磷酸化的定位对应于BBe单层的Myo 9 b敲低区域。这些数据揭示了Myo 9 b在上皮伤口愈合和TJ完整性维持过程中的关键作用，这些关键功能可能在Myo 9 b相关IBD患者中发生改变。
Myo9b is a motor–RhoGAP chimera that has been implicated in inflammatory bowel disease. Findings suggest that Myo9b is essential during both collective and individual wound-induced cell migration. It is also important for maintaining tight junction barrier integrity. Polymorphisms in the gene encoding the heavy chain of myosin IXb (Myo9b) have been linked to several forms of inflammatory bowel disease (IBD). Given that Myo9b contains a RhoGTPase-activating protein domain within its tail, it may play key roles in Rho-mediated actin cytoskeletal modifications critical to intestinal barrier function. In wounded monolayers of the intestinal epithelial cell line Caco2BBe (BBe), Myo9b localizes to the extreme leading edge of lamellipodia of migrating cells. BBe cells exhibiting loss of Myo9b expression with RNA interference or Myo9b C-terminal dominant-negative (DN) tail-tip expression lack lamellipodia, fail to migrate into the wound, and form stress fiber–like arrays of actin at the free edges of cells facing the wound. These cells also exhibit disruption of tight junction (TJ) protein localization, including ZO-1, occludin, and claudin-1. Torsional motility and junctional permeability to dextran are greatly increased in cells expressing DN-tail-tip. Of interest, this effect is propagated to neighboring cells. Consistent with a role for Myo9b in regulating levels of active Rho, localization of both RhoGTP and myosin light chain phosphorylation corresponds to Myo9b-knockdown regions of BBe monolayers. These data reveal critical roles for Myo9b during epithelial wound healing and maintenance of TJ integrity—key functions that may be altered in patients with Myo9b-linked IBD.