Work

Rubicon is a critical regulator of immune barrier integrity and limits enteric pathogen infection

Year: 2026

Type: article

Abstract: Introduction Intestinal immune barrier integrity is governed by coordinated epithelial renewal, junctional organization, and vesicular trafficking. Herein, we identify a previously undefined role for the noncanonical autophagy protein Rubicon in the maintence of the intestinal immune barrier. Rubicon-dependent vesicular pathways, including conjugation of ATG8 proteins to single membranes (CASM) function to support vesicle trafficking homeostasis. Methods Mice with global deletion of Rubicon (Rubcn - / - ) were used to evaluate impact on gut permeability using FITC-dextran, overall intestinal anatomy and histopathology, junction protein homeostasis, and pathogen response. Results and discussion Loss of Rubicon led to impaired intestinal barrier function and increased intestinal permeability, supported by a 10-fold increase in circulating FITC-dextran. Rubicon-deficiency was also associated with multiple anatomical changes including elongation of the small and large intestines, shortened small-intestinal villi, epithelial hyperplasia, and lymphoid expansion, amongst others. Mechanistically, Rubicon-deficiency resulted in aberrant trafficking and mislocalization of key junctional proteins including E-cadherin and occludin. Furthermore, metagenomic analysis of the intestinal microbial community revealed broad restructuring of the intestinal microbiota compared to WT animals. Importantly, Rubicon-deficiency hypersensitized mice to enteric pathogen infection. Rubcn - / - mice exhibited accelerated and worsened mortality in addition to systemic bacteremia following infection with Salmonella Typhimurium . Bacterial burden was significantly in multiple tissues including mesenteric lymph nodes, spleen, and liver, further supporting failure of the intestinal barrier following loss of Rubicon. Collectively, these findings identify Rubicon as a novel and foundational regulator of IEC vesicular processing, epithelial junctional organization, intestinal barrier function, and host defense beyond established roles in innate immune cells.

Source: Frontiers in Immunology

DOI: 10.3389/fimmu.2026.1889997