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

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

Vishnu Mohanan ¹ ², Toru Nakata ¹ ², A Nicole Desch ¹ ², Chloé Lévesque ³, Angela Boroughs ², Gaelen Guzman ¹, Zhifang Cao ², Elizabeth Creasey ², Junmei Yao ², Gabrielle Boucher ³, Guy Charron ³, Atul K Bhan ⁴ ⁵, Monica Schenone ¹, Steven A Carr ¹, Hans-Christian Reinecker ⁵ ⁶, Mark J Daly ¹ ⁵ ⁷, John D Rioux ³ ⁸, Kara G Lassen ⁹ ², Ramnik J Xavier ⁹ ² ⁵ ⁶ ¹⁰

Affiliations

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. [email protected] [email protected].
10 Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

PMID: 29420262 DOI: 10.1126/science.aan0814

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.

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