Overcoming a barrier to IBD Inflammatory bowel disease (IBD) is a group of disorders linked to inflammation of the gastrointestinal tract. Colitis is a type of IBD that affects the inner lining of the colon and has been linked to a gene known as C1orf106. Mohanan et al. found that C1orf106 encodes a protein that stabilizes the integrity of epithelial junctions and enhances barrier defense (see the Perspective by Citi). IBD-associated mutations in C1orf106 lead to greater cytohesin-1 protein levels, changes in E-cadherin localization, and enhanced susceptibility to intestinal pathogens. Modulation of C1orf106 may thus hold promise for treating colitis and other IBDs. Science, this issue p. 1161; see also p. 1097 A protein encoded by a gene linked to colitis affects epithelial barrier function and thereby affects inflammatory bowel disease. 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.

中文翻译：

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C1orf106是一种调节上皮粘附连接稳定性的结肠炎风险基因

克服 IBD 的障碍 炎症性肠病 (IBD) 是一组与胃肠道炎症相关的疾病。结肠炎是一种影响结肠内壁的 IBD，并与一种称为 C1orf106 的基因有关。莫哈南等人。发现 C1orf106 编码一种蛋白质，可以稳定上皮连接的完整性并增强屏障防御（参见花旗的观点）。C1orf106 中 IBD 相关突变导致更高的 cytohesin-1 蛋白水平、E-钙粘蛋白定位的变化以及对肠道病原体的易感性增强。因此，C1orf106 的调节有望用于治疗结肠炎和其他 IBD。科学，这个问题 p。第1161章 另见第。1097 由与结肠炎相关的基因编码的蛋白质会影响上皮屏障功能，从而影响炎症性肠病。C1orf106 中的多态性与炎症性肠病 (IBD) 的风险增加有关。然而，C1orf106 的功能和疾病相关多态性的后果尚不清楚。在这里，我们证明 C1orf106 通过调节 cytohesin-1（一种控制 ARF6 激活的鸟嘌呤核苷酸交换因子）的降解来调节粘附连接稳定性。通过限制细胞粘附素-1 依赖的 ARF6 激活，C1orf106 稳定粘附连接。与该模型一致，C1orf106–/– 小鼠表现出肠上皮细胞屏障缺陷，这是在 IBD 患者中观察到的一种表型，可增加对肠道病原体的易感性。此外，IBD 风险变体会增加 C1orf106 泛素化和周转，从而导致功能障碍。