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. 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

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

Vishnu Mohanan et al. Science. .

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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Conflict of interest statement

Competing interests: The authors declare no competing financial interests.

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