Publication Date:
2013-10-04
Description:
The recognition of autophagy related 16-like 1 (ATG16L1) as a genetic risk factor has exposed the critical role of autophagy in Crohn's disease. Homozygosity for the highly prevalent ATG16L1 risk allele, or murine hypomorphic (HM) activity, causes Paneth cell dysfunction. As Atg16l1(HM) mice do not develop spontaneous intestinal inflammation, the mechanism(s) by which ATG16L1 contributes to disease remains obscure. Deletion of the unfolded protein response (UPR) transcription factor X-box binding protein-1 (Xbp1) in intestinal epithelial cells, the human orthologue of which harbours rare inflammatory bowel disease risk variants, results in endoplasmic reticulum (ER) stress, Paneth cell impairment and spontaneous enteritis. Unresolved ER stress is a common feature of inflammatory bowel disease epithelium, and several genetic risk factors of Crohn's disease affect Paneth cells. Here we show that impairment in either UPR (Xbp1(DeltaIEC)) or autophagy function (Atg16l1(DeltaIEC) or Atg7(DeltaIEC)) in intestinal epithelial cells results in each other's compensatory engagement, and severe spontaneous Crohn's-disease-like transmural ileitis if both mechanisms are compromised. Xbp1(DeltaIEC) mice show autophagosome formation in hypomorphic Paneth cells, which is linked to ER stress via protein kinase RNA-like endoplasmic reticulum kinase (PERK), elongation initiation factor 2alpha (eIF2alpha) and activating transcription factor 4 (ATF4). Ileitis is dependent on commensal microbiota and derives from increased intestinal epithelial cell death, inositol requiring enzyme 1alpha (IRE1alpha)-regulated NF-kappaB activation and tumour-necrosis factor signalling, which are synergistically increased when autophagy is deficient. ATG16L1 restrains IRE1alpha activity, and augmentation of autophagy in intestinal epithelial cells ameliorates ER stress-induced intestinal inflammation and eases NF-kappaB overactivation and intestinal epithelial cell death. ER stress, autophagy induction and spontaneous ileitis emerge from Paneth-cell-specific deletion of Xbp1. Genetically and environmentally controlled UPR function within Paneth cells may therefore set the threshold for the development of intestinal inflammation upon hypomorphic ATG16L1 function and implicate ileal Crohn's disease as a specific disorder of Paneth cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3862182/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3862182/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Adolph, Timon E -- Tomczak, Michal F -- Niederreiter, Lukas -- Ko, Hyun-Jeong -- Bock, Janne -- Martinez-Naves, Eduardo -- Glickman, Jonathan N -- Tschurtschenthaler, Markus -- Hartwig, John -- Hosomi, Shuhei -- Flak, Magdalena B -- Cusick, Jennifer L -- Kohno, Kenji -- Iwawaki, Takao -- Billmann-Born, Susanne -- Raine, Tim -- Bharti, Richa -- Lucius, Ralph -- Kweon, Mi-Na -- Marciniak, Stefan J -- Choi, Augustine -- Hagen, Susan J -- Schreiber, Stefan -- Rosenstiel, Philip -- Kaser, Arthur -- Blumberg, Richard S -- 100140/Wellcome Trust/United Kingdom -- 260961/European Research Council/International -- DK0034854/DK/NIDDK NIH HHS/ -- DK044319/DK/NIDDK NIH HHS/ -- DK051362/DK/NIDDK NIH HHS/ -- DK053056/DK/NIDDK NIH HHS/ -- DK088199/DK/NIDDK NIH HHS/ -- G1002610/Medical Research Council/United Kingdom -- R01 DK044319/DK/NIDDK NIH HHS/ -- R01 DK051362/DK/NIDDK NIH HHS/ -- R01 DK053056/DK/NIDDK NIH HHS/ -- R01 DK088199/DK/NIDDK NIH HHS/ -- England -- Nature. 2013 Nov 14;503(7475):272-6. doi: 10.1038/nature12599. Epub 2013 Oct 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Gastroenterology and Hepatology, Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, UK [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24089213" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Autophagy/genetics
;
Carrier Proteins/genetics/metabolism
;
Cell Line
;
DNA-Binding Proteins/genetics/metabolism
;
Endoplasmic Reticulum Stress/genetics
;
Inflammation
;
Intestinal Diseases/genetics/*physiopathology
;
Intestinal Mucosa/cytology/*pathology
;
Mice
;
Paneth Cells/*pathology
;
Signal Transduction
;
Transcription Factors/genetics/metabolism
;
Unfolded Protein Response/physiology
;
eIF-2 Kinase/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink
