Bertolotti A, Wang X, Novoa I, Jungreis R, Schlessinger K, Cho J H, West A B, Ron D
Skirball Institute of Biomolecular Medicine, Departments of Medicine and Cell Biology, and the Kaplan Cancer Center, New York University School of Medicine, New York, New York, USA.
J Clin Invest. 2001 Mar;107(5):585-93. doi: 10.1172/JCI11476.
The epithelial cells of the gastrointestinal tract are exposed to toxins and infectious agents that can adversely affect protein folding in the endoplasmic reticulum (ER) and cause ER stress. The IRE1 genes are implicated in sensing and responding to ER stress signals. We found that epithelial cells of the gastrointestinal tract express IRE1beta, a specific isoform of IRE1. BiP protein, a marker of ER stress, was elevated in the colonic mucosa of IRE1beta(-/-) mice, and, when exposed to dextran sodium sulfate (DSS) to induce inflammatory bowel disease, mutant mice developed colitis 3-5 days earlier than did wild-type or IRE1beta(+/-) mice. The inflammation marker ICAM-1 was also expressed earlier in the colonic mucosa of DSS-treated IRE1beta(-/-) mice, indicating that the mutation had its impact early in the inflammatory process, before the onset of mucosal ulceration. These findings are consistent with a model whereby perturbations in ER function, which are normally mitigated by the activity of IRE1beta, participate in the development of colitis.
胃肠道上皮细胞会接触到毒素和感染因子，这些物质会对内质网（ER）中的蛋白质折叠产生不利影响并引发内质网应激。肌醇需求酶1（IRE1）基因与内质网应激信号的感知和响应有关。我们发现胃肠道上皮细胞表达IRE1β，它是IRE1的一种特定异构体。BiP蛋白是内质网应激的标志物，在IRE1β基因敲除（IRE1β(-/-)）小鼠的结肠黏膜中水平升高，并且在暴露于葡聚糖硫酸钠（DSS）以诱导炎症性肠病时，突变小鼠比野生型或IRE1β杂合（IRE1β(+/-)）小鼠提前3 - 5天发生结肠炎。炎症标志物细胞间黏附分子1（ICAM-1）在DSS处理的IRE1β(-/-)小鼠的结肠黏膜中也更早表达，这表明该突变在炎症过程早期，即黏膜溃疡发生之前就产生了影响。这些发现与一种模型一致，即通常由IRE1β的活性缓解的内质网功能紊乱参与了结肠炎的发展。
