| First Author | Tschurtschenthaler M | Year | 2017 |
| Journal | J Exp Med | Volume | 214 |
| Issue | 2 | Pages | 401-422 |
| PubMed ID | 28082357 | Mgi Jnum | J:240694 |
| Mgi Id | MGI:5888946 | Doi | 10.1084/jem.20160791 |
| Citation | Tschurtschenthaler M, et al. (2017) Defective ATG16L1-mediated removal of IRE1alpha drives Crohn's disease-like ileitis. J Exp Med 214(2):401-422 |
| abstractText | 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 IRE1alpha. IRE1alpha accumulates in Paneth cells of Atg16l1DeltaIEC mice, and humans homozygous for ATG16L1T300A exhibit a corresponding increase of IRE1alpha in intestinal epithelial crypts. In contrast to a protective role of the IRE1beta isoform, hyperactivated IRE1alpha also drives a similar ileitis developing earlier in life in Atg16l1;Xbp1DeltaIEC mice, in which ER stress is induced by deletion of the unfolded protein response transcription factor XBP1. The selective autophagy receptor optineurin interacts with IRE1alpha, and optineurin deficiency amplifies IRE1alpha levels during ER stress. Furthermore, although dysbiosis of the ileal microbiota is present in Atg16l1;Xbp1DeltaIEC 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 IRE1alpha aggregates during ER stress at this site. |
