AGR2 Is Induced in Asthma and Promotes Allergen-Induced Mucin Overproduction

Mucins are gel-forming proteins that are responsible for the characteristic viscoelastic properties of mucus. Mucin overproduction is a hallmark of asthma, but the cellular requirements for airway mucin production are poorly understood. The endoplasmic reticulum (ER) protein anterior gradient homolog 2 (AGR2) is required for production of the intestinal mucin MUC2, but its role in the production of the airway mucins MUC5AC and MUC5B is not established. Microarray data were analyzed to examine the relationship between AGR2 and MUC5AC expression in asthma. Immunofluorescence was used to localize AGR2 in airway cells. Coimmunoprecipitation was used to identify AGR2-immature MUC5AC complexes. Agr2(-/-) mice were used to determine the role of AGR2 in allergic airway disease. AGR2 localized to the ER of MUC5AC- and MUC5B-producing airway cells and formed a complex with immature MUC5AC. AGR2 expression increased together with MUC5AC expression in airway epithelium from "Th2-high" asthmatics. Allergen-challenged Agr2(-/-) mice had greater than 50% reductions in MUC5AC and MUC5B proteins compared with allergen-challenged wild-type mice. Impaired mucin production in Agr2(-/-) mice was accompanied by an increase in the proportion of mucins contained within the ER and by evidence of ER stress in airway epithelium. This study shows that AGR2 increases with mucin overproduction in individuals with asthma and in mouse models of allergic airway disease. AGR2 interacts with immature mucin in the ER and loss of AGR2 impairs allergen-induced MUC5AC and MUC5B overproduction.

黏蛋白是形成凝胶的蛋白质，负责黏液的特征性黏弹性特性。黏蛋白过度产生是哮喘的一个标志，但对气道黏蛋白产生的细胞需求了解甚少。内质网（ER）蛋白前梯度同源物2（AGR2）是肠道黏蛋白MUC2产生所必需的，但其在气道黏蛋白MUC5AC和MUC5B产生中的作用尚未确定。分析了微阵列数据以研究哮喘中AGR2和MUC5AC表达之间的关系。免疫荧光用于定位气道细胞中的AGR2。共免疫沉淀用于鉴定AGR2 - 未成熟MUC5AC复合物。使用Agr2（-/-）小鼠来确定AGR2在过敏性气道疾病中的作用。AGR2定位于产生MUC5AC和MUC5B的气道细胞的内质网，并与未成熟的MUC5AC形成复合物。在“Th2高”哮喘患者的气道上皮中，AGR2表达与MUC5AC表达一起增加。与过敏原激发的野生型小鼠相比，过敏原激发的Agr2（-/-）小鼠的MUC5AC和MUC5B蛋白减少了50%以上。Agr2（-/-）小鼠黏蛋白产生受损伴随着内质网中所含黏蛋白比例的增加以及气道上皮内质网应激的迹象。这项研究表明，在哮喘患者和过敏性气道疾病小鼠模型中，AGR2随着黏蛋白过度产生而增加。AGR2与内质网中的未成熟黏蛋白相互作用，AGR2的缺失会损害过敏原诱导的MUC5AC和MUC5B过度产生。