Abstract

Cell polarity is essential for spatially regulation of physiological processes in metazoans by which hormonal stimulation‒secretion coupling is precisely coupled for tissue homeostasis and organ communications. However, the molecular mechanisms underlying epithelial cell polarity establishment remain elusive. Here, we show that septin cytoskeleton interacts with catenin complex to organize a functional domain to separate apical from basal membranes in polarized epithelial cells. Using polarized epithelial cell monolayer as a model system with trans-epithelial electrical resistance as functional readout, our studies show that septins are essential for epithelial cell polarization. Our proteomic analyses discovered a novel septin‒catenin complex during epithelial cell polarization. The functional relevance of septin‒catenin complex was then examined in 3D culture in which suppression of septins resulted in deformation of apical lumen in cysts, a hallmark seen in polarity-deficient 3D cultures and animals. Mechanistically, septin cytoskeleton stabilizes the association of adherens catenin complex with actin cytoskeleton, and depletion or disruption of septin cytoskeleton liberates adherens junction and polarity complexes into the cytoplasm. Together, these findings reveal a previously unrecognized role for septin cytoskeleton in the polarization of the apical‒basal axis and lumen formation in polarized epithelial cells.

中文翻译：

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septin 复合物将连环蛋白复合物与肌动蛋白细胞骨架连接起来，以建立上皮细胞的极性

摘要

细胞极性对于后生动物生理过程的空间调节至关重要，激素刺激-分泌耦合通过这种方式精确耦合以实现组织稳态和器官通讯。然而，上皮细胞极性建立的分子机制仍然难以捉摸。在这里，我们展示了 septin 细胞骨架与连环蛋白复合物相互作用，以组织一个功能域，将极化上皮细胞中的顶端与基底膜分开。使用极化上皮细胞单层作为模型系统，以跨上皮电阻作为功能读数，我们的研究表明，败血素对于上皮细胞极化至关重要。我们的蛋白质组学分析在上皮细胞极化过程中发现了一种新的 septin-catenin 复合物。然后在 3D 培养中检查了 septin-catenin 复合物的功能相关性，其中抑制 septin 导致囊肿顶端腔变形，这是在极性缺陷 3D 培养和动物中看到的标志。从机制上讲，septin 细胞骨架稳定了粘附连环蛋白复合物与肌动蛋白细胞骨架的结合，并且 septin 细胞骨架的消耗或破坏将粘附连接和极性复合物释放到细胞质中。总之，这些发现揭示了化粪池细胞骨架在极化上皮细胞的顶-基底轴极化和管腔形成中的先前未被认识的作用。septin 细胞骨架稳定了粘附连环蛋白复合物与肌动蛋白细胞骨架的结合，septin 细胞骨架的消耗或破坏将粘附连接和极性复合物释放到细胞质中。总之，这些发现揭示了化粪池细胞骨架在极化上皮细胞的顶-基底轴极化和管腔形成中的先前未被认识的作用。septin 细胞骨架稳定了粘附连环蛋白复合物与肌动蛋白细胞骨架的结合，septin 细胞骨架的消耗或破坏将粘附连接和极性复合物释放到细胞质中。总之，这些发现揭示了化粪池细胞骨架在极化上皮细胞的顶-基底轴极化和管腔形成中的先前未被认识的作用。