Supported by an educational grant from Essex Chemie, Switzerland, (to M.S.), a research grant from the European Crohn's and Colitis Organisation (ECCO) (to M.S.), a research grant from the Swiss Philanthropy Foundation (to M.S. and G.R.), a research credit from the University of Zurich (to M.S.), research grants from the Swiss National Science Foundation (SNF) (to G.R.) (Grant No. 310030-120312), SRV (Grant No. 320000-114009/1), and the Swiss IBD Cohort (Grant No. 3347CO-108792), by the Zurich Center for Integrative Human Physiology (ZIHP) of the University of Zurich, and by a Senior Research Award from the Crohn's and Colitis Foundation of America (CCFA) (to D.F.M.).
Protein tyrosine phosphatase nonreceptor type 2 regulates autophagosome formation in human intestinal cells†
Version of Record online: 10 OCT 2011
Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.
Inflammatory Bowel Diseases
Volume 18, Issue 7, pages 1287–1302, July 2012
How to Cite
Scharl, M., Wojtal, K. A., Becker, H. M., Fischbeck, A., Frei, P., Arikkat, J., Pesch, T., Kellermeier, S., Boone, D. L., Weber, A., Loessner, M. J., Vavricka, S. R., Fried, M., McCole, D. F. and Rogler, G. (2012), Protein tyrosine phosphatase nonreceptor type 2 regulates autophagosome formation in human intestinal cells. Inflamm Bowel Dis, 18: 1287–1302. doi: 10.1002/ibd.21891
- Issue online: 11 JUN 2012
- Version of Record online: 10 OCT 2011
- Manuscript Accepted: 16 AUG 2011
- Manuscript Received: 19 APR 2011
- Crohn's disease;
Autophagy is a process of central importance for maintaining cell homeostasis, survival, and the regulation of inflammation. Recent studies associated variants within the gene loci, encoding protein tyrosine phosphatase nonreceptor type 2 (PTPN2), and autophagy genes, such as autophagy-related 16-like 1 (ATG16L1), with chronic inflammatory disorders, such as Crohn's disease (CD). We show that PTPN2 regulates autophagy in human intestinal epithelial cells (IEC) and primary colonic lamina propria fibroblasts (CLPF).
Protein analysis in IEC and CLPF was performed by western blotting. Autophagososme formation was assessed by LC3B immunofluorescence or immunohistochemistry. Human intestinal tissue samples were obtained from noninflammatory bowel disease (IBD) control or from CD patients and genotyped for disease-associated PTPN2 or ATG16L1 variations.
Knockdown of PTPN2 causes impaired autophagosome formation and dysfunctional autophagy resulted in increased levels of intracellular Listeria monocytogenes (LM) and elevated IEC apoptosis in response to tumor necrosis factor (TNF) and interferon gamma (IFN-γ). Similar findings were observed in primary CLPF derived from CD patients carrying the CD-associated PTPN2 variant. Presence of the ATG16L1 variant prevented the cytokine-induced rise in PTPN2 protein, finally resulting in impaired LC3B-II levels in IEC. Actively inflamed intestinal biopsies from CD patients carrying either ATG16L1 or PTPN2 genetic variants revealed aberrant LC3B expression patterns when compared with samples from non-IBD control patients.
Our results demonstrate that PTPN2 regulates autophagosome formation in human intestinal cells. We provide a model of how a dysfunction of the CD susceptibility genes, PTPN2 and/or ATG16L1, may contribute to the onset and perpetuation of chronic intestinal inflammation. (Inflamm Bowel Dis 2011;)