BECLIN1, a core component of Class III phosphatidylinositol 3-kinase (PI3KC3) complexes, is well-established as a regulator of autophagy initiation (Complex I) and endocytic trafficking (Complex II). While traditionally studied for its role in autophagy, emerging evidence points to essential autophagy-independent functions of BECLIN1 in maintaining gastrointestinal integrity.
Here, we demonstrate that conditional deletion of BECLIN1 in the adult intestinal epithelium causes rapid-onset fatal enteritis in mice, marked by severe barrier dysfunction, widespread apoptosis, and cellular stress in both the endoplasmic reticulum and mitochondria. Surviving absorptive and secretory epithelial cells displayed morphological abnormalities suggestive of impaired antimicrobial function. Notably, deletion of the core autophagy gene ATG7 did not recapitulate these phenotypes, indicating that BECLIN1 governs intestinal homeostasis through distinct, non-autophagic mechanisms.
Using intestinal organoids derived from BECLIN1- and ATG7-deficient mice, we observed that BECLIN1 loss, but not ATG7 loss, led to disrupted distribution of Rab5-, EEA1-, Rab7-, and LAMP1-positive endosomes and aberrant E-cadherin trafficking. These findings support a key role for BECLIN1 in endocytic trafficking and junctional integrity.
Together, these data reveal a critical and multifaceted role for BECLIN1 in preserving intestinal epithelial architecture and function, driven by both autophagy-dependent and -independent mechanisms. This has important implications for understanding gut pathophysiology in diseases such as inflammatory bowel disease (IBD), where epithelial barrier integrity is compromised.