Targeted deletion of Atg5 in intestinal epithelial cells promotes dextran sodium sulfate-induced colitis

Autophagy-associated genes have been identified as susceptible loci for inflammatory bowel disease. We investigated the role of a core autophagy factor, AtgS, in the development of dextran sodium sulfate (DSS)-induced colitis. Intestinal epithelial cell (IEC)-specific AtgS gene deficient mice (Atg5(Delta IEC) mice) were generated by cross of Atg5-floxed mice (Atg5(fl/fl)) with transgenic mice expressing Cre-recombinase driven by the villin promotor. Mice were given three cycles of 1.5% DSS in drinking water for 5 days and regular water for 14 days over a 60-day period. The dysfunction of autophagy characterized by a marked accumulation of p62 protein, a substrate for autophagy degradation, was detected in epithelial cells in the non-inflamed and inflamed mucosa of inflammatory bowel disease patients. DSS-colitis was exacerbated in Atg5(Delta IEC) mice compared to control Atg5(fl/fl) mice. Phosphorylation of inositol-requiring transmembrane kinase/endonuclease1 alpha (IRE1 alpha), a sensor for endoplasmic reticulum stress, and c-Jun N-terminal kinase, a downstream target of IRE1 alpha, were significantly enhanced in IECs in DSS-treated Atg5(Delta IEC) mice. Accumulation of phosphorylated IRE1 alpha was enhanced by the treatment with chloroquine, an autophagy inhibitor. Apoptotic IECs were more abundant in DSS-treated Atg5(Delta IEC) mice. These findings suggest that AtgS suppresses endoplasmic reticulum stress-induced apoptosis of IECs via the degradation of excess p-IRE1 alpha.