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

Markus Tschurtschenthaler, Timon E Adolph, Jonathan W Ashcroft, Lukas Niederreiter, Richa Bharti, Svetlana Saveljeva, Joya Bhattacharyya, Magdalena B Flak, David Q Shih, Gwenny M Fuhler, Miles Parkes, Kenji Kohno, Takao Iwawaki, C Janneke van der Woude, Heather P Harding, Andrew M Smith, Maikel P Peppelenbosch, Stephan R Targan, David Ron, Philip RosenstielRichard S Blumberg, Arthur Kaser

Research output: Contribution to journalArticlepeer-review

138 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)401-422
Number of pages22
JournalThe Journal of experimental medicine
Volume214
Issue number2
DOIs
Publication statusPublished - Feb 2017

Keywords

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

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