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Defective ATG16L1-mediated removal of IRE1α drives Crohn's disease-like ileitis.

Published version
Peer-reviewed

Type

Article

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Authors

Tschurtschenthaler, M 
Adolph, TE 
Ashcroft, JW 
Niederreiter, L 
Bharti, R 

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 Atg16l1ΔIEC mice, and humans homozygous for ATG16L1T300A exhibit 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;Xbp1ΔIEC mice, 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;Xbp1ΔIEC mice 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.

Description

Keywords

Age Factors, Animals, Autophagy, Autophagy-Related Proteins, Crohn Disease, Endoplasmic Reticulum Stress, Endoribonucleases, Ileitis, Membrane Proteins, Mice, Mice, Inbred C57BL, Microbiota, Protein Serine-Threonine Kinases

Journal Title

Journal of Experimental Medicine

Conference Name

Journal ISSN

0022-1007
1540-9538

Volume Title

214

Publisher

Rockefeller University Press
Sponsorship
Medical Research Council (MR/N001893/1)
European Research Council (648889)
Wellcome Trust (200848/Z/16/Z)
Wellcome Trust (106260/Z/14/Z)
European Research Council (260961)
This study was supported by the European Research Council under the European Community’s Seventh Framework Program (grant FP7/2007-2013)/ERC, agreement no. 260961 to A. Kaser and grant HORIZON2020/ERC, agreement no. 648889 to A. Kaser), the Wellcome Trust (Investigator Award 106260/Z/14/Z to A. Kaser and Principal Research Fellowship 2008/Z/16/Z to D. Ron), the Cambridge Biomedical Research Centre (A. Kaser), a Medical Research Council PhD for clinicians training fellowship (grant MR/N001893/1 to J. Bhattacharyya), fellowships from the European Crohn’s and Colitis Organization (M. Tschurtschenthaler and T.E. Adolph), the Research Training Group Genes, Environment, and Inflammation supported by the Deutsche Forschungsgemeinschaft (grant RTG 1743/1 to P. Rosenstiel), the SFB877 subproject B9 and CLVIII ExC 306 Inflammation at Interfaces (P. Rosenstiel), and the National Institutes of Health (grants DK044319, DK051362, DK053056, and DK088199 to the Harvard Digestive Diseases Center and grant DK0034854 to R.S. Blumberg).