title: Defective ATG16L1-mediated removal of IRE1α drives Crohn's disease-like ileitis.
abstract: ATG16L1T300A, a major risk polymorphism in Crohn's disease (CD), causes impaired autophagy, but it has remained unclear how this predisposes to CD. In this study, we report that mice with Atg16l1 deletion in intestinal epithelial cells (IECs) spontaneously develop transmural ileitis phenocopying ileal CD in an age-dependent manner, driven by the endoplasmic reticulum (ER) stress sensor IRE1α. IRE1α accumulates in Paneth cells of Atg16l1ΔIECmice, and humans homozygous for ATG16L1T300Aexhibit a corresponding increase of IRE1α in intestinal epithelial crypts. In contrast to a protective role of the IRE1β isoform, hyperactivated IRE1α also drives a similar ileitis developing earlier in life in Atg16l1;Xbp1ΔIECmice, in which ER stress is induced by deletion of the unfolded protein response transcription factor XBP1. The selective autophagy receptor optineurin interacts with IRE1α, and optineurin deficiency amplifies IRE1α levels during ER stress. Furthermore, although dysbiosis of the ileal microbiota is present in Atg16l1;Xbp1ΔIECmice as predicted from impaired Paneth cell antimicrobial function, such structural alteration of the microbiota does not trigger ileitis but, rather, aggravates dextran sodium sulfate-induced colitis. Hence, we conclude that defective autophagy in IECs may predispose to CD ileitis via impaired clearance of IRE1α aggregates during ER stress at this site.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, England, UK.
authors.forename: Markus
authors.identifier: 0000-0002-0060-4790
authors.initials: M
authors.lastname: Tschurtschenthaler
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, England, UK.
authors.forename: Timon E
authors.initials: TE
authors.lastname: Adolph
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, England, UK.
authors.forename: Jonathan W
authors.identifier: 0000-0002-6224-4233
authors.initials: JW
authors.lastname: Ashcroft
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, England, UK.
authors.forename: Lukas
authors.initials: L
authors.lastname: Niederreiter
authors.affiliation: Institute for Clinical Molecular Biology, Christian-Albrechts-University Kiel, D-24105 Kiel, Germany.
authors.forename: Richa
authors.identifier: 0000-0001-8271-1268
authors.initials: R
authors.lastname: Bharti
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, England, UK.
authors.forename: Svetlana
authors.identifier: 0000-0002-0644-9752
authors.initials: S
authors.lastname: Saveljeva
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, England, UK.
authors.forename: Joya
authors.identifier: 0000-0003-1745-4167
authors.initials: J
authors.lastname: Bhattacharyya
authors.affiliation: Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Magdalena B
authors.identifier: 0000-0002-8238-9835
authors.initials: MB
authors.lastname: Flak
authors.affiliation: Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: David Q
authors.identifier: 0000-0003-1335-7044
authors.initials: DQ
authors.lastname: Shih
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, 3015 CE Rotterdam, Netherlands.
authors.forename: Gwenny M
authors.initials: GM
authors.lastname: Fuhler
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, England, UK.
authors.forename: Miles
authors.initials: M
authors.lastname: Parkes
authors.affiliation: Laboratory of Molecular and Cell Genetics, Graduate School of Biological Sciences, Nara Institute of Science and Technology, Ikoma, Nara 630-0192, Japan.
authors.forename: Kenji
authors.identifier: 0000-0002-3503-6551
authors.initials: K
authors.lastname: Kohno
authors.affiliation: Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, Kahoku, Ishikawa 920-0293, Japan.
authors.forename: Takao
authors.identifier: 0000-0001-8753-1979
authors.initials: T
authors.lastname: Iwawaki
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, 3015 CE Rotterdam, Netherlands.
authors.forename: C
authors.identifier: 0000-0003-3875-6957
authors.initials: C
authors.lastname: Janneke van der Woude
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0QQ, England, UK.
authors.forename: Heather P
authors.identifier: 0000-0002-7359-7974
authors.initials: HP
authors.lastname: Harding
authors.affiliation: Eastman Dental Institute, University College London, London WC1E 6BT, England, UK.
authors.forename: Andrew M
authors.identifier: 0000-0002-4691-5973
authors.initials: AM
authors.lastname: Smith
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, 3015 CE Rotterdam, Netherlands.
authors.forename: Maikel P
authors.identifier: 0000-0001-9112-6028
authors.initials: MP
authors.lastname: Peppelenbosch
authors.affiliation: Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048.
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Targan
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0QQ, England, UK.
authors.forename: David
authors.identifier: 0000-0002-3014-5636
authors.initials: D
authors.lastname: Ron
authors.affiliation: Institute for Clinical Molecular Biology, Christian-Albrechts-University Kiel, D-24105 Kiel, Germany.
authors.forename: Philip
authors.identifier: 0000-0002-9692-8828
authors.initials: P
authors.lastname: Rosenstiel
authors.affiliation: Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 ak729@cam.ac.uk rblumberg@bwh.harvard.edu.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Blumberg
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, England, UK ak729@cam.ac.uk rblumberg@bwh.harvard.edu.
authors.forename: Arthur
authors.identifier: 0000-0003-1419-3344
authors.initials: A
authors.lastname: Kaser
mesh_terms: D000367:Age Factors; D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins / Q000502:physiology*; D003424:Crohn Disease / Q000209:etiology*; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000502:physiology*; D007079:Ileitis / Q000209:etiology*; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*
chemical_list: C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D008565:Membrane Proteins; C486556:Ern2 protein, mouse; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases