Mucin-2 ER-to-Golgi transport mechanism identifies source of ER stress in inflammatory bowel disease
Morsink, M. A. J.; Koch, L. S.; Hu, S.; Weersma, R. K.; van Goor, H.; Bourgonje, A. R.; Broersen, K.
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The intestinal mucous layer relies on mucin-2 secretion. While the mucin-2 secretory pathway has been studied, endoplasmic reticulum (ER) to Golgi apparatus (Golgi) trafficking remains poorly understood. The size of mucin-2 exceeds the capacity of regular coat protein complex II (COPII) vesicles, responsible for ER-to-Golgi transport. After confirming conventional secretion of mucin-2, we showed that COPII vesicle enlargement is facilitated by TANGO1 and cTAGE5, and promoted by KLHL12. Inflammatory bowel disease (IBD) is characterized by a compromised mucous layer, altered activity of Transforming Growth Factor {beta} (TGF-{beta}), and increased ER stress. Using a cell culture, we showed that TGF-{beta} inhibition induces TANGO1-mediated ER stress. Mucosal gene expression analysis in IBD patients confirmed elevated ER stress and validated concomitantly altered mRNA levels of TGF-{beta} with mucin-2 and transport proteins TANGO1 and cTAGE5. In conclusion, we propose that the unsuccessful formation of enlarged COPII vesicles could be a source of ER stress in IBD, because of lowered TANGO1 protein expression, subsequently leading to decreased mucin-2 secretion.
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