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MUCOSAL ER STRESS Sintesi della relazione

Project ID: 260961
Finanziato nell'ambito di: FP7-IDEAS-ERC
Paese: United Kingdom

Final Report Summary - MUCOSAL ER STRESS (XBP1 and Endoplasmic Reticulum Stress in Mucosal Homeostasis)

In this grant we have investigated how endoplasmic reticulum (ER) stress in the intestinal epithelium is involved in inflammatory bowel disease. ER stress occurs when proteins are misfolded, hence do not adopt the shape that is required for their proper functioning. ER stress instigates the unfolded protein response (UPR), to resolve such stress via adapting the protein translation and folding machinery and via removing misfolded proteins. ER stress is a common occurrence in the intestinal epithelium of Crohn’s disease and ulcerative colitis, the two main forms of inflammatory bowel disease. The intestinal epithelium is the single cell layer that lines the inner surface of the intestinal tract, and separates it from the ‘inner outside’ world with its abundance of microbial life (the intestinal microbiota), food, metabolites and potential toxins that pass through our intestinal tract. With protein folding an active process, the intestinal epithelium is particularly exposed to factors that might disrupt proper protein folding.
We have discovered that ER stress, triggered via genetic deletion of the UPR transcription factor XBP1 in the intestinal epithelium, induces autophagy in Paneth cells, a specialist intestinal epithelial cell type located at the base of small intestinal crypts. Autophagy is a fundamental cell biological process that engulfs intracellular material and degrades it. One of Crohn’s disease main genetic risk factors, ATG16L1T300A, leads to impaired autophagy function. We could demonstrate that impaired function of autophagy leads to ER stress in Paneth cells. As a consequence, we discovered that co-impairment of XBP1 and ATG16L1 in the intestinal epithelium leads to spontaneous ileitis, closely resembling the histological features of ileal Crohn’s disease. We could further demonstrate that the inflammation that arises from ER stress in the intestinal epithelium actually originates from Paneth cells. We identified a critical role of a specific sensor of ER stress, IRE1alpha, which orchestrates induction of Crohn’s disease-like ileitis when autophagy function is impaired. We delineated the involvement of the intestinal microbiota and its altered composition in intestinal inflammation in this model, as our model of spontaneous Crohn’s-like ileitis afforded the first opportunity for mechanistic interrogation in the context of studies focusing on a major Crohn’s disease risk gene.
We could further demonstrate that ER stress is critically involved in regulating the function of intestinal stem cells and the regenerative response of the intestinal epithelium. ER stress caused an expansion of intestinal stem cells in a mechanism that involved IRE1alpha overactivation in Paneth cells, and increased proliferative output from the so-called transit amplifying zone of the intestinal epithelium, which was dependent on a mechanism that involved IL-6 and STAT3 signalling. In turn, this had profound consequences on the propensity to form tumours, both in a model of colitis-associated cancer, and in a genetic model based on a mutation in the Adenomatous Polyposis Coli (APC) gene.
Altogether, we have revealed the critical role that ER stress plays in the development of Crohn’s disease and ulcerative colitis.


Renata Schaeffer, (EC Awards Manager)
Tel.: +44122333543
Fax: +441223332988
Numero di registrazione: 184718 / Ultimo aggiornamento: 2016-06-27