Format

Send to

Choose Destination
Mol Biol Cell. 2016 Feb 1;27(3):483-90. doi: 10.1091/mbc.E15-10-0724. Epub 2015 Dec 2.

Epithelial Sel1L is required for the maintenance of intestinal homeostasis.

Author information

1
Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853 Graduate Program in Biochemistry, Molecular and Cell Biology, Cornell University, Ithaca, NY 14853 ss2475@cornell.edu lq35@cornell.edu.
2
Immunity, Infection and Inflammation Program, Mater Medical Research Institute, Mater Health Services, South Brisbane, Queensland 4101, Australia.
3
Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853.
4
Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853.
5
Graduate Program in Genetics, Genomics and Development, Cornell University, Ithaca, NY 14853.
6
Department of Microbiology, Cornell University, Ithaca, NY 14853 Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853.
7
Graduate Program in Genetics, Genomics and Development, Cornell University, Ithaca, NY 14853 Department of Microbiology, Cornell University, Ithaca, NY 14853 Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853.
8
Laboratory Animal Research Center, Medical College of Soochow University, Suzhou 215006, Jiangsu, China.
9
Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853.
10
Department of Clinical Science, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

Abstract

Inflammatory bowel disease (IBD) is an incurable chronic idiopathic disease that drastically decreases 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, whereas 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.

PMID:
26631554
PMCID:
PMC4751599
DOI:
10.1091/mbc.E15-10-0724
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center