未折叠蛋白反应在肠道生理学中的重要作用。

eGastroenterology Pub Date : 2024-12-31 eCollection Date: 2024-10-01 DOI:10.1136/egastro-2024-100129
Claudio Hetz, Juan Francisco Silva-Agüero, Lisa M Ellerby
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引用次数: 0

摘要

肠上皮是宿主和微生物群之间的重要接口,调节先天和适应性免疫,营养物质的吸收和全身代谢,并介导与神经系统的双向交流。由于肠上皮暴露于动态变化和充满微生物的肠道环境中,以及多种上皮细胞(特别是杯状细胞、肠内分泌细胞和Paneth细胞)为适应肠道和系统生理需要而产生的高分泌需求,肠上皮不断受到蛋白质静止机制的挑战。在所有情况下,肠细胞都需要活跃的未折叠蛋白反应(UPR)来维持其生理功能,这是监测和调节环境中分泌功能变化的主要途径。一种特殊的内质网(ER)应激传感器,被称为肌醇要求跨膜激酶/核糖核酸内切酶β,在肠上皮内稳态、调节粘液产生和与微生物群的交流中具有特殊作用。慢性内质网应激或影响关键UPR介质的基因突变,除了结肠癌外,还会导致炎症性肠病和溃疡性结肠炎的发生。在这里,我们回顾了将UPR和内质网应激与肠道生理和肠道疾病联系起来的最新进展。还讨论了缓解内质网应激或加强UPR功能以改善衰老和肠道疾病中肠道功能的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Essential roles of the unfolded protein response in intestinal physiology.

The intestinal epithelium serves as an essential interface between the host and microbiota, regulating innate and adaptive immunity, absorption of nutrients and systemic metabolism, and mediating bidirectional communication with the nervous system. The intestinal epithelium suffers constant challenges to the proteostasis machinery due to its exposure to the dynamically changing and microbial laden lumenal gut environment and to the high secretory demand placed on multiple epithelial cell types to accommodate gut and systemic physiology-especially goblet, enteroendocrine and Paneth cells. In all cases, intestinal cells require an active unfolded protein response (UPR) to sustain their physiological function, the main pathway that monitors and adjusts secretory function changes in the environment. A specialised endoplasmic reticulum (ER) stress sensor uniquely expressed in epithelial cells lining mucosal surfaces, termed inositol-requiring transmembrane kinase/endoribonuclease β, has specific roles in intestinal epithelial homeostasis, regulating mucus production and communication with microbiota. Chronic ER stress or genetic mutations affecting key UPR mediators contribute to the occurrence of inflammatory bowel disease and ulcerative colitis, in addition to colon cancer. Here, we review recent advances linking the UPR and ER stress with gut physiology and intestinal disease. Therapeutic strategies to alleviate ER stress or enforce UPR function to improve intestinal function in ageing and in bowel diseases are also discussed.

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