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Science. 2018 Mar 9;359(6380):1161-1166. doi: 10.1126/science.aan0814. Epub 2018 Feb 1.

C1orf106 is a colitis risk gene that regulates stability of epithelial adherens junctions.

Author information

1
The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
2
Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
3
Montreal Heart Institute Research Center, Montreal, Quebec H1T 1C8, Canada.
4
Pathology Department, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
5
Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114, USA.
6
Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
7
Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
8
Department of Medicine, Université de Montréal, Montreal, Quebec H1T 1C8, Canada.
9
The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. klassen@broadinstitute.org xavier@molbio.mgh.harvard.edu.
10
Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Abstract

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 adherens junction stability by regulating the 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 observed in IBD patients that confers increased susceptibility to intestinal pathogens. Furthermore, the IBD risk variant increases C1orf106 ubiquitination and turnover with consequent functional impairments. 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.

PMID:
29420262
PMCID:
PMC6008784
DOI:
10.1126/science.aan0814
[Indexed for MEDLINE]
Free PMC Article

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