O'Mara Maurice, Zhang Suisheng, Knaus Ulla G
Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland.
Nat Commun. 2025 Jul 25;16(1):6868. doi: 10.1038/s41467-025-62272-1.
Well-organized repair of damaged barrier epithelia is vital for infection control, resolution of inflammation, and enduring physical protection. Cysteine thiol and methionine oxidation are connected to cytoskeletal rearrangements in cell migration and wound healing, but how localized redox signaling is achieved to regulate dynamic processes remains elusive. Here, we identify DUOX2, a mucosal barrier NADPH oxidase, as vesicle-incorporated HO source, localizing to sites of cytoskeletal reorganization, and facilitating tunneling nanotube and lamellipodia formation. Using traceable fluorescent DUOX2 and the membrane-bound HO sensor HyPer7-MEM enabled insight into DUOX2 vesicle trafficking and HO generation at sites of actin polymerization and dynamic remodeling. Stable expression or ablation confirmed DUOX2 generated HO as a catalyst for cell-cell connections, random motility and directed migration. We identify a signaling axis from the mechanosensor PIEZO1 to DUOX2 and FER tyrosine kinase activation to initiate retraction wave-mediated efficient wound closure in epithelial cells, a prerequisite for barrier integrity.
受损屏障上皮组织的有序修复对于控制感染、消除炎症和提供持久的物理保护至关重要。半胱氨酸硫醇和甲硫氨酸氧化与细胞迁移和伤口愈合过程中的细胞骨架重排有关，但局部氧化还原信号如何实现以调节动态过程仍不清楚。在这里，我们确定了DUOX2，一种粘膜屏障NADPH氧化酶，作为囊泡结合的HO来源，定位于细胞骨架重组部位，并促进隧道纳米管和片状伪足的形成。使用可追踪的荧光DUOX2和膜结合的HO传感器HyPer7-MEM能够深入了解DUOX2囊泡运输以及肌动蛋白聚合和动态重塑部位的HO生成。稳定表达或敲除证实DUOX2产生HO作为细胞间连接、随机运动和定向迁移的催化剂。我们确定了一个从机械传感器PIEZO1到DUOX2以及FER酪氨酸激酶激活的信号轴，以启动回缩波介导的上皮细胞高效伤口闭合，这是屏障完整性的先决条件。
