Tschurtschenthaler, M;
Adolph, TE;
Ashcroft, JW;
Niederreiter, L;
Bharti, R;
Saveljeva, S;
Bhattacharyya, J;
... Kaser, A; + view all
(2017)
Defective ATG16L1-mediated removal of IRE1α drives Crohn's disease-like ileitis.
J Exp Med
10.1084/jem.20160791.
(In press).
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Abstract
ATG16L1(T300A), 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 Atg16l1(ΔIEC) mice, and humans homozygous for ATG16L1(T300A) 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;Xbp1(ΔIEC) 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;Xbp1(ΔIEC) 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.
| Type: | Article |
|---|---|
| Title: | Defective ATG16L1-mediated removal of IRE1α drives Crohn's disease-like ileitis. |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1084/jem.20160791 |
| Publisher version: | http://dx.doi.org/10.1084/jem.20160791 |
| Additional information: | © 2017 Tschurtschenthaler et al. This article is distributed under the terms of an Attribution– Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http ://www .rupress .org /terms /). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https :// creativecommons .org /licenses /by -nc -sa /4 .0 /). |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Eastman Dental Institute |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1537281 |
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