Work

Non-canonical FOXO1 signaling governs epithelial barrier integrity through spatial regulation of the E-cadherin–β-catenin complex

Year: 2026

Type: article

Abstract: The epithelial barrier serves as a critical defense against bacterial invasion that is traditionally thought to be disrupted by transcriptional or proteolytic turnover of adherens junctions. Here, we reveal a striking, non-canonical mechanism of barrier failure in which the transcription factor FOXO1 mediates rapid bacteria-induced loss of barrier function independent of gene transcription or proteolysis. Using a 3D microfluidic device and an in vivo murine model, we demonstrate that bacteria or lipopolysaccharide trigger dramatic relocalization of FOXO1 to the nucleus with subsequent redistribution of E-cadherin from the membrane to the cytoplasm, resulting in an increase in epithelial leakiness. Furthermore, we found that stimulation increased FOXO1 binding to β-catenin and enhanced β-catenin Tyr654 phosphorylation, which were accompanied by disruption of the β-catenin–E-cadherin complex and destabilization of epithelial barrier integrity. Nuclear-restricted FOXO1 expression alone is sufficient to replicate bacterial effects and induce barrier failure, while cytoplasmic retention or epithelial-specific Foxo1 deletion rescues barrier function and preserves membrane-localized E-cadherin and β-catenin despite bacterial challenge. These findings define a FOXO1–β-catenin–E-cadherin spatiotemporal axis as a previously unrecognized rapid-response mechanism controlling epithelial barrier integrity. Bacterial challenge rapidly weakens epithelial barriers through a non-canonical, FOXO1–β-catenin–E-cadherin axis that disrupts adherens junctions and redistributes E-cadherin independently of transcription or proteolysis.

Source: Nature Communications

DOI: 10.1038/s41467-026-78640-4