BECLIN-1 is essential for the maintenance of gastrointestinal epithelial integrity by regulating endocytic trafficking, F-actin organization, and lysosomal function.

Abstract

Disrupted intestinal homeostasis and barrier function contribute to the development of diseases such as inflammatory bowel disease. BECLIN-1, a core component of two class III phosphatidylinositol 3 kinase complexes, has a dual role in autophagy and endocytic trafficking. Emerging evidence suggests that its endocytic trafficking function is essential for intestinal integrity. To investigate the fatal gastrointestinal phenotype observed in BECLIN-1 knockout mice, we used organoids derived from these animals to show that BECLIN-1 deletion disrupts the localization of CADHERIN1/ECADHERIN to adherens junctions and OCCLUDIN to tight junctions. Impaired cargo trafficking to the lysosome was also observed. Filamentous actin cytoskeleton also became disorganized though there were no changes in its spatial interaction with CATENIN BETA1/BETA-CATENIN nor in BETA-CATENIN localization. The trafficking defects were all less pronounced or absent in organoids lacking an autophagy-only regulator, ATG7, emphasizing BECLIN-1's trafficking role in maintaining gut homeostasis and barrier function. These findings advance our understanding of epithelial dysfunction and the mechanisms underlying intestinal diseases.