The protein disulfide isomerase AGR2 is essential for production of intestinal mucus
The protein disulfide isomerase AGR2 is essential for production of intestinal mucus
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蛋白质二硫键异构酶 AGR2 对于肠粘液的产生至关重要
DOI：
10.1073/pnas.0808722106
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发表时间：
2009-04-28
影响因子：
11.1
通讯作者：
Erle, David J.
中科院分区：
文献类型：
--
作者：
Park, Sung-Woo;Zhen, Guohua;Erle, David J.
蛋白质二硫键异构酶（PDI）通过催化内质网（ER）中半胱氨酸二硫键的形成和改组来帮助蛋白质折叠和组装。PDI家族的许多成员在哺乳动物中表达，但对特定PDI在体内的作用知之甚少。最近基于同源性的搜索其他PDI家族成员确定了前梯度同源物2（AGR2），一种最初推测由肠上皮细胞分泌的蛋白质。在这里，我们表明，AGR2是存在于ER的肠分泌上皮细胞，是必不可少的在体内生产的肠粘蛋白MUC2，一个大的，富含半胱氨酸的糖蛋白，形成保护性粘液凝胶内衬肠。AGR2硫氧还蛋白样结构域内的半胱氨酸残基与MUC2形成混合二硫键，表明AGR2在粘蛋白加工中的直接作用。缺乏AGR2的小鼠是可行的，但对结肠炎高度敏感，这表明AGR2在保护免受疾病方面起着关键作用。我们的结论是AGR2是PDI家族的一个独特成员，在肠道粘液产生中具有专门的和非冗余的作用。
Protein disulfide isomerases (PDIs) aid protein folding and assembly by catalyzing formation and shuffling of cysteine disulfide bonds in the endoplasmic reticulum (ER). Many members of the PDI family are expressed in mammals, but the roles of specific PDIs in vivo are poorly understood. A recent homology-based search for additional PDI family members identified anterior gradient homolog 2 (AGR2), a protein originally presumed to be secreted by intestinal epithelial cells. Here, we show that AGR2 is present within the ER of intestinal secretory epithelial cells and is essential for in vivo production of the intestinal mucin MUC2, a large, cysteine-rich glycoprotein that forms the protective mucus gel lining the intestine. A cysteine residue within the AGR2 thioredoxin-like domain forms mixed disulfide bonds with MUC2, indicating a direct role for AGR2 in mucin processing. Mice lacking AGR2 were viable but were highly susceptible to colitis, indicating a critical role for AGR2 in protection from disease. We conclude that AGR2 is a unique member of the PDI family, with a specialized and nonredundant role in intestinal mucus production.