Science:C1orf106变异增加IBD风险的机制是什么

Science

2/1/18Report

37.205

影响因子

原标题:C1orf106是调节上皮黏着连接稳定性的结肠炎风险基因

① C1orf106的多态性与炎症性肠病(IBD)的风险增加相关;② C1orf106通过调控cytohesin-1的降解来调节黏着连接的稳定性,cytohesin-1是一种控制ARF6活化的鸟嘌呤核苷酸交换因子;③ 通过限制cytohesin-1依赖性的ARF6活化,C1orf106可稳定黏着连接;④ 敲除C1orf106可导致小鼠肠道上皮细胞屏障缺陷,这与在IBD患者中观察到的对肠道病原体易感性增加的表型一致;⑤ IBD风险相关的C1orf106基因变异加速C1orf106的降解并缩短其半衰期,引发功能障碍。

黏着连接 炎症性肠病(IBD) C1orf106多态性

图片

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

DOI:
10.1126/science.aan0814

Abstract & Authors展开

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.

All Authors:
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 Reinecker, Mark J Daly, John D Rioux, Kara G Lassen, Ramnik J Xavier

First Authors:
Vishnu Mohanan

Correspondence:
Kara G Lassen, Ramnik J Xavier

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