Title |
Epithelial Sel1L is required for the maintenance of intestinal homeostasis
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Published in |
Molecular Biology of the Cell, December 2015
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DOI | 10.1091/mbc.e15-10-0724 |
Pubmed ID | |
Authors |
Shengyi Sun, Rohan Lourie, Sara B. Cohen, Yewei Ji, Julia K. Goodrich, Angela C. Poole, Ruth E. Ley, Eric Y. Denkers, Michael A. McGuckin, Qiaoming Long, Gerald E. Duhamel, Kenneth W. Simpson, Ling Qi |
Abstract |
Inflammatory bowel disease (IBD) is an incurable chronic idiopathic disease that drastically decreases the quality of life. Endoplasmic reticulum (ER)-associated degradation (ERAD) is responsible for the clearance of misfolded proteins; however, its role in disease pathogenesis remains largely unexplored. Here we show that the expression of SEL1L and HRD1, the most conserved branch of mammalian ERAD, is significantly reduced in ileal Crohn's disease (CD). Consistent with this observation, laboratory mice with enterocyte-specific Sel1L deficiency (Sel1L(ΔIEC)) develop spontaneous enteritis and have increased susceptibility to Toxoplasma gondii-induced ileitis. This is associated with profound defects in Paneth cells and a disproportionate increase of Ruminococcus gnavus, a mucolytic bacterium with known association with CD. Surprisingly, while both ER stress sensor IRE1α and effector CHOP are activated in the small intestine of Sel1L(ΔIEC) mice, they are not solely responsible for ERAD deficiency-associated lesions seen in the small intestine. Thus, our study points to a constitutive role of Sel1L-Hrd1 ERAD in epithelial cell biology and the pathogenesis of intestinal inflammation in CD. |
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