MassIVE MSV000081941

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The colitis risk gene C1orf106 (ROCS) regulates epithelial adherens junction stability

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Description

Mohanan V, Nakata T, Desch N, L�vesque C, Boroughs A, Guzman G, Cao Z, Creasey E, Yao J, Boucher G, Charron G, Bhan AK, Schenone M, Carr SA, Reinecker HC, Daly MJ, Rioux JD, Lassen KG, Xavier RJ. Science 2018. Single nucleotide polymorphisms in C1orf106 are associated with increased risk of inflammatory bowel disease (IBD). However, the function of C1orf106 and the consequences of disease-associated polymorphisms are unknown. Here we demonstrate that C1orf106 regulates the stability of adherens junctions by regulating ubiquitin-mediated degradation of cytohesin-1, a guanine nucleotide exchange factor that controls activation of ARF6. By limiting cytohesin-1-dependent ARF6 activation, C1orf106 stabilizes adherens junctions. Consistent with this model, C1orf106-/- mice exhibit defects in the intestinal epithelial cell barrier, a phenotype also observed in IBD patients and that confers increased susceptibility to intestinal pathogens. Furthermore, we find that the IBD risk variant C1orf106 *333F shows increased ubiquitination and turnover with consequent impairments in function. These findings delineate a mechanism by which a genetic polymorphism fine-tunes intestinal epithelial barrier integrity and elucidate a fundamental mechanism of cellular junctional control. [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: inflammatory bowel disease ; iTRAQ

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Principal Investigators:
(in alphabetical order) 		Steven A. Carr, Broad Institute of MIT and Harvard, United States
Submitting User: clauser
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