Tuberous sclerosis complex 1 (Tsc1) is a tumor suppressor that functions together with Tsc2 to negatively regulate the mechanistic target of rapamycin complex 1 (mTORC1) activity. Here, we show that Tsc1 has a critical role in the tight junction (TJ) formation of epithelium, independent of its role in Tsc2 and mTORC1 regulation. When an epithelial cell establishes contact with neighboring cells, Tsc1, but not Tsc2, migrates from the cytoplasm to junctional membranes, in which it binds myosin 6 to anchor the perijunctional actin cytoskeleton to β-catenin and ZO-1. In its absence, perijunctional actin cytoskeleton fails to form. In mice, intestine-specific or inducible, whole-body Tsc1 ablation disrupts adherens junction/TJ structures in intestine or skin epithelia, respectively, causing Crohn’s disease–like symptoms in the intestine or psoriasis-like phenotypes on the skin. In patients with Crohn’s disease or psoriasis, junctional Tsc1 levels in epithelial tissues are markedly reduced, concomitant with the TJ structure impairment, suggesting that Tsc1 deficiency may underlie TJ-related diseases. These findings establish an essential role of Tsc1 in the formation of cell junctions and underpin its association with TJ-related human diseases.

结节性硬化症复合物 1 (Tsc1) 是一种肿瘤抑制因子，它与 Tsc2 一起发挥负调控雷帕霉素复合物 1 (mTORC1) 活性的机制靶点的作用。在这里，我们表明 Tsc1 在上皮细胞的紧密连接 (TJ) 形成中具有关键作用，与其在 Tsc2 和 mTORC1 调节中的作用无关。当上皮细胞与相邻细胞建立联系时，Tsc1 而不是 Tsc2，从细胞质迁移到连接膜，在其中它结合肌球蛋白 6 将连接周围肌动蛋白细胞骨架锚定到 β-连环蛋白和 ZO-1。在它不存在的情况下，结周肌动蛋白细胞骨架无法形成。在小鼠中，肠道特异性或可诱导的全身 Tsc1 消融分别破坏了肠道或皮肤上皮细胞中的粘附连接/TJ 结构，导致肠道出现克罗恩病样症状或皮肤出现银屑病样表型。在克罗恩病或银屑病患者中，上皮组织中的连接 Tsc1 水平显着降低，同时伴有 TJ 结构损伤，这表明 Tsc1 缺乏可能是 TJ 相关疾病的基础。这些发现确立了 Tsc1 在细胞连接形成中的重要作用，并巩固了其与 TJ 相关人类疾病的关联。