Biology subjects

Juliani, J.

Publications and source records attributed to Juliani, J..

3 recordsLinked to original sources

bioRxiv2025

Sufficient levels of BECLIN1 are required for intestinal epithelial cell homeostasis and protection against unwanted intestinal inflammation

The prototypical autophagy regulator BECLIN1, orchestrates both autophagic and endocytic trafficking, and its homozygous deletion in the intestinal epithelium leads to intestinal disruption bearing similarities to inflammatory bowel disease (IBD). However, complete loss of BECLIN1 is rare in human disease. To model the effects of a partial reduction in BECLIN1, we examined mice with a monoallelic deletion of Becn1 in the intestinal epithelium, which decreased BECLIN1 protein levels by approximately 50%. Unlike the fatal phenotype following homozygous Becn1 deletion, the heterozygous mice were grossly normal, though they presented with significantly shorter small intestines. Gastrointestinal organoids derived from the mice also displayed disrupted endocytic trafficking and altered cytoskeletal dynamics resulting in mislocalisation of junctional proteins such as E-CADHERIN. In the mice, these changes were associated with impaired goblet cell function and maturation accompanied by abnormal mucin production, composition and secretion, resulting in compromised mucus barrier integrity. The mice also exhibited heightened susceptibility to dextran sulfate sodium (DSS)-induced colitis, emphasising the critical role of BECLIN1 in mediating protection against unregulated inflammation. Investigation of BECLIN1 levels in biopsies from patients with inflammatory bowel disease (IBD) revealed changes in its expression across distinct states of inflammation with reduced levels observed in highly inflamed regions in some patients, consistent with the gastrointestinal defects seen in mice with reduced BECLIN1. Hence, this study provides crucial insights into the multifaceted importance of BECLIN1 sufficiency in the intestinal epithelium to prevent pathophysiology. This highlights the potential of BECLIN1 as a biomarker and therapeutic target for IBD management.

cell biology↗

bioRxiv2024

BECLIN-1 is Essential for the Maintenance of Gastrointestinal Epithelial Integrity by Regulating Endocytic Trafficking, F-actin Organization and Lysosomal Function

Disrupted intestinal homeostasis and barrier function are key contributors to the development of various diseases, including inflammatory bowel disease (IBD). BECLIN-1, a core component of two class III phosphatidylinositol 3-kinase (PtdIns3K) complexes, has a dual role in autophagy and endocytic trafficking. Emerging evidence suggests it is involved in maintaining intestinal integrity which involves its endocytic trafficking function. To gain insights into the fatal gastrointestinal (GI) phenotype observed in BECLIN-1 knockout adult mice, organoids derived from these animals were used to investigate the role of BECLIN-1 in GI epithelial function. BECLIN-1 deletion led to disrupted localization of CADHERIN-1/E-CADHERIN to adherens junctions (AJs) and OCCLUDIN to tight junctions (TJs), resulting in the mislocalization of these critical barrier proteins. Lysosomal dysfunction was also observed, characterized by impaired cargo degradation. In addition, the filamentous actin (F-actin) cytoskeleton became disorganized though this was not associated with changes in the interaction between F-actin and CATENIN BETA-1/BETA-CATENIN nor in alterations in BETA-CATENIN localization, though BETA-CATENIN levels were reduced. These effects were all less pronounced or absent in organoids lacking the autophagy-only regulator ATG7 (autophagy related 7), further emphasizing the involvement of BECLIN-1s protein trafficking role in the maintenance of gut homeostasis and barrier function. These findings provide new insights into processes involved in epithelial dysfunction, deepening our understanding of mechanisms underlying intestinal disease.

cell biology↗

bioRxiv2023

Beclin1 is essential for intestinal homeostasis.

BECLIN1 is a component of Class III phosphatidylinositol 3-kinase complexes that orchestrates autophagy initiation and endocytic trafficking. Here we show intestinal epithelium-specific BECLIN1 deletion in adult mice led to rapid fatal enteritis with compromised gut barrier integrity, highlighting its intrinsic critical role in gut maintenance. BECLIN1-deficient intestinal epithelial cells exhibited extensive apoptosis, impaired autophagy, and stressed endoplasmic reticulum and mitochondria. Remaining absorptive enterocytes and secretory cells displayed morphological abnormalities. Deletion of the autophagy regulator, ATG7, failed to elicit similar effects, suggesting novel autophagy-independent functions of BECLIN1 distinct from ATG7. Indeed, organoids derived from BECLIN1 KO mice showed E-cadherin mislocalisation providing a mechanism linking endocytic trafficking mediated by Beclin1 and loss of intestinal barrier integrity. Our findings establish an indispensable role of BECLIN1 in maintaining mammalian intestinal homeostasis and uncover its involvement in endocytic trafficking in this process. Hence, this study has significant implications for our understanding of intestinal pathophysiology.

cell biology↗