Details Unfold: The Endoplasmic Reticulum Stress Response in Intestinal Inflammation and Cancer
Details Unfold: The Endoplasmic Reticulum Stress Response in Intestinal Inflammation and Cancer
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细节揭晓：肠道炎症和癌症中的内质网应激反应
DOI：
10.1053/j.gastro.2014.06.013
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发表时间：
2014
期刊：
影响因子：
29.4
通讯作者：
Parker A
中科院分区：
文献类型：
--
作者：
Parker A
肠损伤和上皮细胞损失后，上皮细胞的快速再生对于维持屏障完整性和宿主防御至关重要。然而，对损伤的不受限制的增殖反应可能促进肠道肿瘤的发展。越来越多的证据揭示了肠道炎症、肿瘤发生和细胞应激反应机制（如内质网（ER）应激反应）缺陷之间的联系。由炎症、感染、损伤或高蛋白质周转引起的异常蛋白质在ER中的积累触发了一组应激反应信号传导途径，统称为未折叠蛋白反应（UPR）。UPR通路的激活导致各种机制的上调，以恢复细胞内稳态或诱导细胞凋亡，如果压力仍然没有得到解决。因此，有效的UPR对于维持肠上皮中的稳态特别重要，肠上皮是频繁炎症和损伤的部位，并且含有具有高蛋白质周转的细胞，例如分泌杯状细胞和潘氏细胞。已知UPR途径组分的遗传变异会导致炎症性肠病，包括结肠炎相关癌症（CAC）和结直肠癌（CRC）。在本文讨论的论文中，Niederreiter及其同事探索了这种关联的机制，发现转录因子X-box结合蛋白1（Xbp 1），UPR的效应物，在ER应激期间调节局部炎症并限制增殖和再生反应以抑制肠道肿瘤的发展和进展2013 210（10）：2041-56）。在ER应激条件下，转录因子Xbp 1启动细胞保护性应答，包括蛋白伴侣的上调和增强的ER相关蛋白降解（ERAD）以恢复细胞稳态。为了探索UPR在肠上皮细胞（IEC）中的特定作用，Kaser及其同事先前通过靶向删除Xbp 1产生了一种模拟肠上皮细胞中ER应激的转基因小鼠模型。小鼠IEC中的Xbp 1敲除破坏UPR并导致自发性肠炎和对诱导的结肠炎的易感性增加（Cell 2008，134：743-756）。
Following intestinal injury and epithelial cell loss, rapid regeneration of the epithelium is essential to maintain barrier integrity and host defence. However, an unrestrained proliferative response to injury may promote the development of intestinal tumours. Accumulating evidence reveals links between intestinal inflammation, tumourigenesis, and defects in cellular stress response mechanisms such as the endoplasmic reticulum (ER) stress response. Accumulation of aberrant proteins in the ER resulting from inflammation, infection, injury or high protein turnover triggers a set of stress response signalling pathways collectively termed the unfolded protein response (UPR). Activation of UPR pathways leads to upregulation of various mechanisms to restore cellular homeostasis or induce apoptosis if stress remains unresolved. An effective UPR is therefore particularly important for maintaining homeostasis in the intestinal epithelium, which is a site of frequent inflammation and injury and which contains cells with high protein turnover such as secretory goblet cells and Paneth cells. Genetic variants of UPR pathway components are known to confer risk to inflammatory bowel disease, including colitis-associated cancer (CAC) and colorectal cancer (CRC). In the paper here discussed, Niederreiter and colleagues explore the mechanism for this association, finding that the transcription factor X-box binding protein 1 (Xbp1), an effector of the UPR, acts to regulate local inflammation during ER-stress and restricts proliferative and regenerative responses to inhibit intestinal tumour development and progression (J Exp Med. 2013 210 (10): 2041-56).Under conditions of ER-stress, the transcription factor Xbp1 initiates cytoprotective responses including upregulation of protein chaperones and enhanced ER-associated protein degradation (ERAD) to restore cellular homeostasis. To explore the specific role of the UPR in intestinal epithelial cells (IEC), Kaser and colleagues had previously generated a transgenic mouse model mimicking ER-stress in intestinal epithelia by targeted deletion of Xbp1. Xbp1 knockout in mouse IECs disrupts the UPR and results in spontaneous enteritis and increased susceptibility to induced colitis (Cell 2008, 134: 743-756).