title: Epithelial Sel1L is required for the maintenance of intestinal homeostasis.
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.
authors.affiliation: 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.
authors.forename: Shengyi
authors.initials: S
authors.lastname: Sun
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Medical Research Institute, Mater Health Services, South Brisbane, Queensland 4101, Australia.
authors.forename: Rohan
authors.initials: R
authors.lastname: Lourie
authors.affiliation: Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853.
authors.forename: Sara B
authors.initials: SB
authors.lastname: Cohen
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853.
authors.forename: Yewei
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Graduate Program in Genetics, Genomics and Development, Cornell University, Ithaca, NY 14853.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Goodrich
authors.affiliation: Department of Microbiology, Cornell University, Ithaca, NY 14853 Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853.
authors.forename: Angela C
authors.initials: AC
authors.lastname: Poole
authors.affiliation: 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.
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Ley
authors.affiliation: Department of Microbiology and Immunology, Cornell University, Ithaca, NY 14853.
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Denkers
authors.affiliation: Immunity, Infection and Inflammation Program, Mater Medical Research Institute, Mater Health Services, South Brisbane, Queensland 4101, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McGuckin
authors.affiliation: Laboratory Animal Research Center, Medical College of Soochow University, Suzhou 215006, Jiangsu, China.
authors.forename: Qiaoming
authors.initials: Q
authors.lastname: Long
authors.affiliation: Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853.
authors.forename: Gerald E
authors.initials: GE
authors.lastname: Duhamel
authors.affiliation: Department of Clinical Science, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Simpson
authors.affiliation: 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.
authors.forename: Ling
authors.initials: L
authors.lastname: Qi
mesh_terms: D000818:Animals; D017209:Apoptosis; D004386:Duodenum / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D060746:Endoplasmic Reticulum-Associated Degradation; D004722:Endoribonucleases / Q000502:physiology; D004751:Enteritis / Q000378:metabolism / Q000473:pathology; D020895:Enterocytes / Q000378:metabolism*; D005260:Female; D000069196:Gastrointestinal Microbiome; D057895:Haploinsufficiency; D006706:Homeostasis; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019879:Paneth Cells / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011506:Proteins / Q000502:physiology*; D051742:Transcription Factor CHOP / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: C497250:Ddit3 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C492169:Sel1h protein, mouse; D051742:Transcription Factor CHOP; C498235:Syvn1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases