Vogel Georg F, Klee Katharina M C, Janecke Andreas R, Müller Thomas, Hess Michael W, Huber Lukas A
Division of Cell Biology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria Division of Histology and Embryology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Division of Cell Biology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria Institute of Molecular Biology, University of Innsbruck, 6020 Innsbruck, Austria Center for Molecular Biosciences Innsbruck, University of Innsbruck, 6020 Innsbruck, Austria.
J Cell Biol. 2015 Nov 9;211(3):587-604. doi: 10.1083/jcb.201506112.
Mutations in the motor protein Myosin Vb (Myo5B) or the soluble NSF attachment protein receptor Syntaxin 3 (Stx3) disturb epithelial polarity and cause microvillus inclusion disease (MVID), a lethal hereditary enteropathy affecting neonates. To understand the molecular mechanism of Myo5B and Stx3 interplay, we used genome editing to introduce a defined Myo5B patient mutation in a human epithelial cell line. Our results demonstrate a selective role of Myo5B and Stx3 for apical cargo exocytosis in polarized epithelial cells. Apical exocytosis of NHE3, CFTR (cystic fibrosis transmembrane conductance regulator), and GLUT5 required an interaction cascade of Rab11, Myo5B, Slp4a, Munc18-2, and Vamp7 with Stx3, which cooperate in the final steps of this selective apical traffic pathway. The brush border enzymes DPPIV and sucrase-isomaltase still correctly localize at the apical plasma membrane independent of this pathway. Hence, our work demonstrates how Myo5B, Stx3, Slp4a, Vamp7, Munc18-2, and Rab8/11 cooperate during selective apical cargo trafficking and exocytosis in epithelial cells and thereby provides further insight into MVID pathophysiology.
运动蛋白肌球蛋白Vb（Myo5B）或可溶性NSF附着蛋白受体Syntaxin 3（Stx3）的突变会扰乱上皮极性，并导致微绒毛包涵体病（MVID），这是一种影响新生儿的致命遗传性肠病。为了了解Myo5B和Stx3相互作用的分子机制，我们使用基因组编辑技术在人上皮细胞系中引入了一个明确的Myo5B患者突变。我们的结果表明，Myo5B和Stx3在极化上皮细胞的顶端货物胞吐作用中具有选择性作用。NHE3、CFTR（囊性纤维化跨膜传导调节因子）和GLUT5的顶端胞吐作用需要Rab11、Myo5B、Slp4a、Munc18-2和Vamp7与Stx3的相互作用级联，它们在这一选择性顶端运输途径的最后步骤中协同作用。刷状缘酶DPPIV和蔗糖酶-异麦芽糖酶仍能独立于该途径正确定位于顶端质膜。因此，我们的工作展示了Myo5B、Stx3、Slp4a、Vamp7、Munc18-2和Rab8/11在上皮细胞选择性顶端货物运输和胞吐过程中的协同作用，从而为MVID的病理生理学提供了进一步的见解。
Zotero 插件
