Defective hydration of airway surface mucosa is associated with lung infection in cystic fibrosis (CF), partly caused by disruption of the epithelial barrier integrity. Although rehydration of the CF airway surface liquid (ASL) alleviates epithelium vulnerability to infection by junctional protein expression, the mechanisms linking ASL to barrier integrity are unknown. We show here the strong degradation of YAP1 and TAZ proteins in well-polarized CF human airway epithelial cells (HAECs), a process that was prevented by ASL rehydration. Conditional silencing of YAP1 in rehydrated CF HAECs indicated that YAP1 expression was necessary for the maintenance of junctional complexes. A higher plasma membrane tension in CF HAECs reduced endocytosis, concurrent with the maintenance of active β1-integrin ectopically located at the apical membrane. Pharmacological inhibition of β1-integrin accumulation restored YAP1 expression in CF HAECs. These results indicate that dehydration of the CF ASL affects epithelial plasma membrane tension, resulting in ectopic activation of a β1-integrin/YAP1 signaling pathway associated with degradation of junctional proteins.

中文翻译：

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心尖脱水通过 β1-整合素/YAP1 途径损害囊性纤维化气道上皮屏障。

气道表面粘膜水合缺陷与囊性纤维化（CF）肺部感染有关，部分原因是上皮屏障完整性破坏。尽管 CF 气道表面液体 (ASL) 的补液通过连接蛋白表达减轻了上皮对感染的脆弱性，但将 ASL 与屏障完整性联系起来的机制尚不清楚。我们在此展示了极化良好的 CF 人气道上皮细胞 (HAEC) 中 YAP1 和 TAZ 蛋白的强烈降解，而 ASL 补液可阻止这一过程。再水化的 CF HAEC 中YAP1的条件沉默表明 YAP1 的表达对于维持连接复合物是必需的。 CF HAEC 中较高的质膜张力减少了内吞作用，同时维持异位位于顶膜的活性β1-整合素。 β1-整合素积累的药理学抑制可恢复 CF HAEC 中 YAP1 的表达。这些结果表明，CF ASL 脱水影响上皮质膜张力，导致与连接蛋白降解相关的 β1-整合素/YAP1 信号通路异位激活。