is a colitis risk gene that regulates stability of epithelial adherens junctions.
Polymorphisms in 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, 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.
|Year of Publication||
2018 03 09
|PubMed Central ID||
U19 AI109725 / AI / NIAID NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
R01 DK068181 / DK / NIDDK NIH HHS / United States
U01 DK062432 / DK / NIDDK NIH HHS / United States
R01 DK064869 / DK / NIDDK NIH HHS / United States
R01 AI113333 / AI / NIAID NIH HHS / United States
R01 DK091247 / DK / NIDDK NIH HHS / United States