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

• Published in: Journal of Clinical Biochemistry and Nutrition Vol. 68; no. 2; pp. 156 - 163
• Main Authors: Inatomi, Osamu, Kume, Shinji, Nishino, Kyohei, Andoh, Akira, Imai, Takayuki, Nishida, Atsushi, Kawahara, Masahiro, Maegawa, Hiroshi
• Format: Journal Article
• Language: English
• Published: Japan SOCIETY FOR FREE RADICAL RESEARCH JAPAN 01.03.2021; Japan Science and Technology Agency; the Society for Free Radical Research Japan
• Subjects: Accumulation; Apoptosis; Autophagy; c-Jun protein; Chloroquine; Colitis; Degradation; Dextran; Dextrans; Drinking water; Endoplasmic reticulum; Epithelial cells; Gene deletion; IBD; Inflammatory bowel disease; Inflammatory bowel diseases; Inositol; Intestine; IRE1α; JNK protein; Kinases; Mucosa; Original; p62 Protein; Phagocytosis; Phosphorylation; Recombinase; Rodents; Sodium sulfate; Substrates; Sulfates; Transcription factors; Transgenic mice; IBD; autophagy; IRE1α
• ISSN: 0912-0009; 1880-5086; 1880-5086
• DOI: 10.3164/jcbn.20-90

Autophagy-associated genes have been identified as susceptible loci for inflammatory bowel disease. We investigated the role of a core autophagy factor, Atg5, in the development of dextran sodium sulfate (DSS)-induced colitis. Intestinal epithelial cell (IEC)-specific Atg5 gene deficient mice (Atg5ΔIEC mice) were generated by cross of Atg5-floxed mice (Atg5fl/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 Atg5ΔIEC mice compared to control Atg5fl/fl mice. Phosphorylation of inositol-requiring transmembrane kinase/endonuclease1α (IRE1α), a sensor for endoplasmic reticulum stress, and c-Jun N-terminal kinase, a downstream target of IRE1α, were significantly enhanced in IECs in DSS-treated Atg5ΔIEC mice. Accumulation of phosphorylated IRE1α was enhanced by the treatment with chloroquine, an autophagy inhibitor. Apoptotic IECs were more abundant in DSS-treated Atg5ΔIEC mice. These findings suggest that Atg5 suppresses endoplasmic reticulum stress-induced apoptosis of IECs via the degradation of excess p-IRE1α.