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

Vishnu Mohanan, Toru Nakata, A. Nicole Desch, Chloé Lévesque, Angela Boroughs, Gaelen Guzman, Zhifang Cao, Elizabeth Creasey, Junmei Yao, Gabrielle Boucher, Guy Charron, Atul K. Bhan, Monica Schenone, Steven A. Carr, Hans–Christian C. Reinecker, Mark J. Daly, John D. Rioux, Kara G. Lassen, Ramnik J. Xavier

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1161-1166
Number of pages6
JournalScience
Volume359
Issue number6380
DOIs
StatePublished - Mar 9 2018
Externally publishedYes

ASJC Scopus subject areas

  • General

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