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

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

SUBMITTER: Tschurtschenthaler M 

PROVIDER: S-EPMC5294857 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature